Novel piperidine derivatives for use in the treatment of chemokine medicated disease states

ABSTRACT

The present invention provides a compound of a formula (I): wherein the variables are defined herein; to a process for preparing such a compound; and to the use of such a compound in the treatment of a chemokine (such as CCR3) or H1 mediated disease state.

The present invention concerns piperidine derivatives havingpharmaceutical activity, to processes for preparing such derivatives, topharmaceutical compositions comprising such derivatives and to the useof such derivatives as active therapeutic agents.

Pharmaceutically active piperidine derivatives are disclosed inWO99/38514, WO99/04794 and WO00/35877.

Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formedfrom histidine by histidine decarboxylase. It is found in most tissuesof the body, but is present in high concentrations in the lung, skin andin the gastrointestinal tract. At the cellular level inflammatory cellssuch as mast cells and basophils store large amounts of histamine. It isrecognised that the degranulation of mast cells and basophils and thesubsequent release of histamine is a fundamental mechanism responsiblefor the clinical manifestation of an allergic process. Histamineproduces its actions by an effect on specific histamine G-proteincoupled receptors, which are of three main types, H1, H2 and H3.Histamine H1 antagonists comprise the largest class of medications usedin the treatment of patients with allergic disorders, such as rhinitisand urticaria. H1 antagonists are useful in controlling the allergicresponse by for example blocking the action of histamine onpost-capillary venule smooth muscle, resulting in decreased vascularpermeability, exudation and oedema. The antagonists also produceblockade of the actions of histamine on the H1 receptors on c-typenociceptive nerve fibres, resulting in decreased itching and sneezing.

Viral infections are known to cause lung inflammation. It has been shownexperimentally that the common cold increases mucosal output of eotaxinin the airways. Instillation of eotaxin into the nose can mimic some ofthe signs and symptoms of a common cold. (See, Greiff L et al Allergy(1999) 54(11) 1204-8 [Experimental common cold increase mucosal outputof eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch.Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin by normalairway epithelial cells after virus A infection].)

Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract macrophages, T cells, eosinophils, basophils andneutrophils to sites of inflammation and also play a role in thematuration of cells of the immune system. Chemokines play an importantrole in immune and inflammatory responses in various diseases anddisorders, including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Thesesmall secreted molecules are a growing superfamily of 8-14 kDa proteinscharacterised by a conserved four cysteine motif. The chemokinesuperfamily can be divided into two main groups exhibitingcharacteristic structural motifs, the Cys-X-Cys (C-X-C, or α) andCys-Cys (C—C, or β) families. These are distinguished on the basis of asingle amino acid insertion between the NH-proximal pair of cysteineresidues and sequence similarity.

The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

The present invention provides a compound of formula (I):

wherein:

-   X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³;-   Y is a bond, C₁₋₆ alkylene (optionally substituted by C₁₋₄ alkyl or    phenyl), phenylene (optionally substituted by halogen, hydroxy, C₁₋₄    alkyl or C₁₋₄ alkoxy) or heterocyclylene (optionally substituted by    halogen, hydroxy, C₁₋₄ alkyl or C₁₋₄ alkoxy);-   Z is CO₂R^(b), NHS(O)₂CF₃, S(O)₂OH, OCH₂CO₂R^(b) or tetrazolyl;-   R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl;-   R² is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl;-   R^(a) and R^(b) are, independently, hydrogen or C₁₋₄ alkyl; or when    R² is aryl or heterocyclyl R^(a) may be C₂₋₃ alkylene forming a ring    with an ortho position on R²;-   R^(c) is hydrogen or hydroxy;-   wherein, unless stated otherwise, the foregoing aryl and    heterocyclyl moieties are optionally substituted by: halogen, cyano,    nitro, hydroxy, oxo, S(O)_(p)R⁴, OC(O)NR⁵R⁶, NR⁷R⁸, NR⁹C(O)R¹⁰,    NR¹¹C(O)NR¹²R¹³, S(O)₂NR¹⁴R¹⁵, NR¹⁶S(O)₂R¹⁷, C(O)NR¹⁸R¹⁹, C(O)R²⁰,    CO₂R²¹, NR²²CO₂R²³, C₁₋₆ alkyl, CF₃, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆    alkoxy, OCF₃, C₁₋₆ alkoxy(C₁₋₆)alkoxy, C-6 alkylthio, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl (itself optionally substituted by    C₁₋₄ alkyl or oxo), methylenedioxy, difluoromethylenedioxy, phenyl,    phenyl(C₁₋₄)alkyl, phenoxy, phenylthio, phenyl(C₁₋₄)alkoxy,    heterocyclyl, heterocyclyl(C₁₋₄)alkyl, heterocyclyloxy or    heterocyclyl(C₁₋₄)alkoxy; wherein any of the immediately foregoing    phenyl and heterocyclyl moieties are optionally substituted with    halogen, hydroxy, nitro, S(O)_(q)(C₁₋₄ alkyl), S(O)₂NH₂,    S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may    join to form a ring as described for R⁵ and R⁶ below), cyano, C₁₋₄    alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂    (and these alkyl groups may join to form a ring as described for R⁵    and R⁶ below), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl),    NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃;-   p and q are, independently, 0, 1 or 2;-   R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁸, R¹⁹,    R²⁰, R²¹ and R²² are, independently, hydrogen, C₁₋₆ alkyl    (optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),    CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen,    hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkyl    groups may join to form a ring as described for R⁵ and R⁶ below),    S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄    alkyl)₂ (and these alkyl groups may join to form a ring as described    for R⁵ and R⁶ below), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,    C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may    join to form a ring as described for R⁵ and R⁶ below), CO₂H,    CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄    alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionally substituted    by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and    these alkyl groups may join to form a ring as described for R⁵ and    R⁶ below), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),    S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring    as described for R⁵ and R⁶ below), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,    C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl    groups may join to form a ring as described for R⁵ and R⁶ below),    CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),    C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);-   alternatively NR⁵R⁶, NR⁷R⁸, NR¹²R¹³, NR¹⁴R¹⁵, NR¹⁸R¹⁹, may,    independently, form a 4-7 membered heterocyclic ring, azetidine,    pyrrolidine, piperidine, azepine, morpholine or piperazine, the    latter optionally substituted by C₁₋₄ alkyl on the distal nitrogen;    R⁴, R¹⁷ and R²³ are, independently, C₁₋₆ alkyl (optionally    substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆    alkenyl), phenyl (itself optionally substituted by halogen, hydroxy,    nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkyl groups    may join to form a ring as described for R⁵ and R⁶ above),    S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄    alkyl)₂ (and these alkyl groups may join to form a ring as described    for R⁵ and R⁶ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,    C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may    join to form a ring as described for R⁵ and R⁶ above), CO₂H,    CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄    alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionally substituted    by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and    these alkyl groups may join to form a ring as described for R⁵ and    R⁶ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),    S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring    as described for R⁵ and R⁶ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,    C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl    groups may join to form a ring as described for R⁵ and R⁶ above),    CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),    C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);    or an N-oxide thereof; or a pharmaceutically acceptable salt    thereof; or a solvate thereof.

Certain compounds of the present invention can exist in differentisomeric forms (such as enantiomers, diastereomers, geometric isomers ortautomers). The present invention covers all such isomers and mixturesthereof in all proportions.

Suitable salts include acid addition salts such as a hydrochloride,dihydrochloride, hydrobromide, sulfate, phosphate, acetate, diacetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate,ethanesulfonate or p-toluenesulfonate. Salts also include metal salts,such as an alkali metal salt (for example a sodium or potassium salt) oran alkaline earth metal salt (for example magnesium or calcium).

The compounds of the invention may exist as solvates (such as hydrates)and the present invention covers all such solvates.

Halogen includes fluorine, chlorine, bromine and iodine. Halogen is, forexample, fluorine or chlorine.

Alkyl groups and moieties are straight or branched chain and comprise,for example, 1 to 6 (such as 1 to 4) carbon atoms. Examples of alkylgroups are methyl, ethyl, n-propyl, iso-propyl or tert-butyl.

Alkylene is a straight carbon chain of 1 to 6 carbons, which isoptionally substituted. Alkylene includes CH₂ or CH₂CH₂, and whensubstituted by alkyl (for example) it can be CH(CH₃) or CH₂C(CH₃)₂.

Alkenyl groups comprise, for example, 2 to 6 (such as 2 to 4) carbonatoms. Examples of alkenyl groups are vinyl or allyl.

Alkynyl groups comprise, for example, 2 to 6 (such as 2 to 4) carbonatoms. An example of an alkynyl group is propargyl.

In one embobiment cycloalkyl groups comprise from 3 to 10 (such as 3 to8, for example 3 to 6) carbon atoms and are mono-, bi or tricyclic.Cycloalkyl is, for example, cyclopropyl, cyclopentyl, cyclohexyl,norbornyl or camphoryl. The cycloalkyl ring is optionally fused to abenzene ring (for example forming a bicyclo[4.2.0]octa-1,3,5-trienyl orindanyl ring system).

In another embodiment cycloalkenyl comprises from 3 to 8 (such as from 3to 6) carbon atoms and is, for example, monocyclic. Cycloalkenyl is, forexample, cyclopentenyl or cyclohexenyl.

Aryl includes phenyl or naphthyl.

Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring,optionally fused to one or more other rings, comprising at least oneheteroatom selected from the group comprising nitrogen, oxygen andsulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl),pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl,isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl,dihydropyridinyl (for example in a 6-oxo-1,6-dihydro-pyridinyl moiety),pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known asbenzfuryl), benz[b]thienyl (also known as benzthienyl orbenzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in a1-dioxo-2,3-dihydrobenz[b]thienyl moiety), indazolyl, benzimidazolyl,benztriazolyl, benzoxazolyl, benzthiazolyl (for example in a1H-benzthiazol-2-one-yl moiety), 2,3-dihydrobenzthiazolyl (for examplein a 2,3-dihydrobenzthiazol-2-one-yl moiety), 1,2,3-benzothiadiazolyl,an imidazopyridinyl (such as imidazo[1,2a]pyridinyl),thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known asbenzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (alsoknown as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl(for example in a coumarinyl or a chromonyl moiety),3,4-dihydro-1H-2,1-benzothiazinyl (for example in a2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl moiety), a pyrazolopyridine(for example 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in a3,7-dihydro-purin-2,6-dione-8-yl moiety), quinolinyl, isoquinolinyl,dihydroisoquinolinyl (for example in a 2H-isoquinolin-1-one-yl moiety),a naphthyridinyl (for example [1,6]naphthyridinyl or[1,8]naphthyridinyl), a dihydro[1,8]naphthyridinyl (for example in a1H-[1,8]naphthyridin-4-one-yl moiety), a benzothiazinyl, adihydrobenzothiazinyl (for example in a 4H-benzo[1,4]thiazin-3-one-ylmoiety), benzo[d]imidazo[2,1-b]thiazol-2-yl or dibenzothiophenyl (alsoknown as dibenzothienyl); or an N-oxide thereof, or an S-oxide orS-dioxide thereof.

An N-oxide of a compound of formula (I) is, for example, a 1-oxy-[1,4′]bipiperidinyl-1′-yl compound.

Phenylene is a phenyl ring joining the carbon to which, inter alia, R²is attached, and the group Z (such as in Example 42 below).

Heterocyclylene is a heterocyclyl ring joining the carbon to which,inter alia, R² is attached, and the group Z (such as in Example 48below). Heterocyclylene is, for example, pyridyl or oxazolyl.

When R² is aryl or heterocyclyl and R^(a) is C₂₋₃ alkylene which forms aring with an ortho position on R² the resulting compound comprises, forexample, an indene ring system. (See, for example, Example 41.)

Phenyl(C₁₋₄ alkyl) is, for example, benzyl or 2-phenyleth-1-yl.

Phenyl(C₁₋₄ alkoxy) is, for example, benzyloxy or 2-phenyleth-1-yloxy.

Heterocyclyl(C₁₋₄ alkyl) is, for example, pyridylmethyl or2-pyridyleth-1-yl.

Heterocyclyl(C₁₋₄ alkoxy) is, for example, pyridyloxy or2-pyridyleth-1-yloxy.

In one particular aspect the invention provides a compound of formula(Ia):

wherein:

-   X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³;-   Y is a bond, C₁₋₆ alkylene (optionally substituted by C₁₋₄ alkyl or    phenyl) or phenylene (optionally substituted by halogen, hydroxy,    C₁₋₄ alkyl or C₁₋₄ alkoxy);-   R^(a) and R^(b) are, independently, hydrogen or C₁₋₄ alkyl;-   R^(c) is hydrogen or hydroxy;-   R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl;-   R² is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl;-   wherein, unless stated otherwise, the foregoing aryl and    heterocyclyl moieties are optionally substituted by: halogen, cyano,    nitro, hydroxy, oxo, S(O)_(p)R⁴, OC(O)NR⁵R⁶, NR⁷R⁸, NR⁹C(O)R¹⁰,    NR¹¹C(O)NR¹²R¹³, S(O)₂NR¹⁴R¹⁵, NR¹⁶S(O)₂R¹⁷, C(O)NR¹⁸R¹⁹, C(O)R²⁰,    CO₂R²¹, NR²²CO₂R²³, C₁₋₆ alkyl, CF₃, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆    alkoxy, OCF₃, C₁₋₆ alkoxy(C₁₋₆)alkoxy, C₁₋₆ alkylthio, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl (itself optionally substituted by    C₁₋₄ alkyl or oxo), methylenedioxy, difluoromethylenedioxy, phenyl,    phenyl(C₁₋₄)alkyl, phenoxy, phenylthio, phenyl(C₁₋₄)alkoxy,    heterocyclyl, heterocyclyl(C₁₋₄)alkyl, heterocyclyloxy or    heterocyclyl(C₁₋₄)alkoxy; wherein any of the immediately foregoing    phenyl and heterocyclyl moieties are optionally substituted with    halogen, hydroxy, nitro, S(O)_(q)(C₁₋₄ alkyl), S(O)₂NH₂,    S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may    join to form a ring as described for R⁵ and R⁶ below), cyano, C₁₋₄    alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂    (and these alkyl groups may join to form a ring as described for R⁵    and R⁶ below), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl),    NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃;-   p and q are, independently, 0, 1 or 2;-   R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁸, R¹⁹,    R²⁰, R²¹ and R²² are, independently, hydrogen, C₁₋₆ alkyl    (optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),    CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen,    hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄    alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and    these alkyl groups may join to form a ring as described for R⁵ and    R⁶ below), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄    alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form    a ring as described for R⁵ and R⁶ below), CO₂H, CO₂(C₁₋₄ alkyl),    NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or    OCF₃) or heterocyclyl (itself optionally substituted by halogen,    hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄    alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and    these alkyl groups may join to form a ring as described for R⁵ and    R⁶ below), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄    alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form    a ring as described for R⁵ and R⁶ below), CO₂H, CO₂(C₁₋₄ alkyl),    NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or    OCF₃);-   alternatively NR⁵R⁶, NR⁷R⁸, NR¹²R¹³, NR¹⁴R¹⁵, NR¹⁸R¹⁹, may,    independently, form a 4-7 membered heterocyclic ring, azetidine,    pyrrolidine, piperidine, azepine, morpholine or piperazine, the    latter optionally substituted by C₁₋₄ alkyl on the distal nitrogen;    R⁴, R¹⁷ and R²³ are, independently, C₁₋₆ alkyl (optionally    substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆    alkenyl), phenyl (itself optionally substituted by halogen, hydroxy,    nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkyl groups    may join to form a ring as described for R⁵ and R⁶ above),    S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄    alkyl)₂ (and these alkyl groups may join to form a ring as described    for R⁵ and R⁶ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,    C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may    join to form a ring as described for R⁵ and R⁶ above), CO₂H,    CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄    alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionally substituted    by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and    these alkyl groups may join to form a ring as described for R⁵ and    R⁶ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),    S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring    as described for R⁵ and R⁶ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,    C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl    groups may join to form a ring as described for R⁵ and R⁶ above),    CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),    C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);-   or an N-oxide thereof; or a pharmaceutically acceptable salt    thereof; or a solvate thereof.

In another aspect the invention provides a compound wherein X is O.

In yet another aspect R¹ is phenyl optionally substituted (for exampleindependently mono- or di-substituted) with halogen (for examplechlorine or fluorine), C₁₋₄ alkyl (for example methyl) or C₁₋₄ alkoxy(for example methoxy).

In a further aspect R¹ is phenyl optionally substituted (for examplewith one, two or three of the same or different) with fluorine,chlorine, C₁₋₄ alkyl (for example methyl) or C₁₋₄ alkoxy (for examplemethoxy). In a still further aspect R¹ is phenyl substituted by one, twoor three (for example two or three) substituents independently selectedfrom: fluorine, chlorine and methyl. For example R¹ is3,4-dichlorophenyl, 2,4-dichloro-3methylphenyl,3,4-dichloro-2-methylphenyl, 2,4-dichlorophenyl, 4-chloro-2-methylphenylor 2-chloro-4-fluorophenyl.

In another aspect R^(a) is hydrogen.

In another aspect R^(b) is hydrogen or methyl.

In another aspect R^(c) is hydrogen.

In a further aspect R² is unsubstituted phenyl or naphthyl, mono-, di-or tri-substituted phenyl or naphthyl or mono-substituted heterocyclyl,the substituents being chosen from those described above.

Heterocyclyl is, for example, pyrimidinyl or pyridinyl. In a furtheraspect of the invention heterocyclyl is optionally substituted by C₁₋₄alkyl or C₁₋₄ alkoxy.

In another aspect R² is hydrogen or phenyl optionally substituted by:halogen (for example fluoro), C₁₋₆ alkyl, C₁₋₆ alkoxy or (C₁₋₆alkyl)C(O)NH.

In a further aspect the present invention provides a compound of formula(I) wherein X is O; R¹ is phenyl optionally substituted by halogen (forexample chlorine) or C₁₋₄ alkyl (for example methyl); and R^(a), R^(b),R^(c) and R² is as defined above.

In a still further aspect the present invention provides a compoundwherein Y is a bond or alkylene (optionally substituted by C₁₋₄ alkyl);R^(a) is hydrogen; and, R² is hydrogen, C₁₋₆ alkyl, phenyl (optionallysubstituted by halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or NHC(O)(C₁₋₄ alkyl))or heterocyclyl (optionally substituted by halogen, C₁₋₄ alkyl or C₁₋₄alkoxy).

In another aspect the present invention provides a compound wherein Y isphenylene (optionally substituted by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy)or heterocyclylene (optionally substituted by halogen, C₁₋₄ alkyl orC₁₋₄ alkoxy); R^(a) is hydrogen; and R² is hydrogen or C₁₋₄ alkyl.

When Z is tetrazolyl it is, for example, tetrazol-5-yl. In yet anotheraspect of the invention Z is CO₂R^(b), wherein R^(b) is hydrogen or C₁₋₄alkyl (for example methyl).

The compounds of the invention can be prepared by adaptation of methodsknown in the art, by adaptation of the Examples given below or by usingor adapting the methods in Scheme 1 {in which EDCI is ethyldimethylaminopropyl carbodiimide; HOBT is 1-hydroxybenzotriazolehydrate; and DMAP is N,N-dimethylaminopyridine}.

A compound of formula (I), for example wherein R^(a) is hydrogen and Zis CO₂R^(b), can be prepared by coupling a compound of formula (II):

with a compound of formula (III):

wherein L is a suitable leaving group (such as halogen (such as chloroor bromo), C₁₋₆ alkylsulfonyl (such as mesylate) or tosylate) and thecoupling can be carried out in a suitable solvent (such as water orN,N-dimethylformamide) at ambient temperature.

Alternatively, a compound of formula (I), wherein R^(a) is hydrogen andZ is CO₂R^(b), can be prepared by reductive amination of a compound (II)with a compound of formula (IV):

wherein R^(b) is C₁₋₄ alkyl, in the presence of NaBH(OAc)₃ and aceticacid, or NaBH₃CN in a suitable solvent (such as tetrahydrofuran),optionally followed by hydrolysis of the ester group.

Alternatively, a compound of formula (I), wherein Y is a bond, R^(a) andR^(b) are both hydrogen and Z is CO₂H, can be prepared by a threecomponent coupling of a compound of formula (II) with compounds offormula (V) and (VI):

in a suitable solvent (such as a C₁₋₆ aliphatic alcohol (for exampleethanol)) at a suitable elevated temperature (for example reflux; suchas 60-100° C.).

A compound of formula (II) can be prepared by deprotecting a compound offormula (VII):

for example using trifluoroacetic acid in a suitable solvent (such asdichloromethane) or using a source of hydrogen chloride in a suitablesolvent (such as dioxane).

A compound of formula (VII), wherein R^(c) is hydrogen, can be preparedby reacting a compound of formula (VI):

with a compound of formula (IX):

in the presence of NaBH(OAc)₃ and acetic acid, in a suitable solvent(such as tetrahydrofuran or dichloromethane).

A compound of formula (VII), wherein R^(c) is hydroxy, can be preparedby reacting a compound of formula (VIII) with a compound of formula (X):

in a suitable solvent (such as a C₁₋₆ aliphatic alcohol, for exampleethanol) at room temperature.

A compound of formula (I), wherein Y is a bond and Z is CO₂H, can beprepared by performing a nitrile hydrolysis on a compound of formula(XI):

Such a hydrolysis can be carried out by refluxing a mixture ofhydrochloric acid and ethanol; or by adding MeSO₃H, water andhydrochloric acid and then refluxing the mixture.

A compound of formula (XI) can be used to form a compound of formula (I)wherein Z is tetrazol-5-yl by reacting it with (CH₃)₃SiN₃ and (Bu₃Sn)₂Oat an elevated temperature (for example in toluene at reflux).

A compound of formula (XI) can be reduced to form a compound of formula(XII):

using sodium borohydride and cobalt (II) chloride in methanol. Acompound of formula (XII) can then be reacted with triflic anhydride ata reduced temperature (for example −78° C. in dichloromethane) to formthe corresponding compound where Z is NHS(O)₂CF₃.

A compound of formula (XI) can be prepared by reacting a compound offormula (II) with R^(a)R²C(O) and titanium isopropoxide (Ti(OiPr)₄),followed by Et₂AlCN. Longer chain variants of the compound of formula(XI) can be made by reacting a compound of formula (II) with: a compoundHal-(CH₂)_(n)CN in the presence of a base (such as potassium carbonate)in acetone; or CH₂═CH—CN in the presence of a base (such as potassiumcarbonate) in acetone; wherein Hal is chlorine, bromine or iodine.

The preparation of various intermediates can be found in WO00/66559 andWO010/77101; alternatively they can be prepared by using or adaptingliterature methods.

Compounds of formula (III) to (IX) can be prepared by using or adaptingmethods described in the art. The preparation of various phenoxypiperidines is described in WO 01/77101.

A compound of formula (I), wherein Y is CHR^(d); R^(d) is hydrogen, C₁₋₄alkyl or phenyl; and Z is CO₂R^(b), can be prepared by reacting acompound of formula (II) with an alkene of formulaR²R^(a)C═CHR^(d)CO₂R^(b) in a suitable solvent, such as ethanol, at asuitable elevated temperature, such as 50-100° C.

A compound of formula (I), wherein R^(a) is hydrogen, Y is CH₂ and Z isCO₂R^(b), can be prepared by reacting a compound of formula (It) with analkyne of formula R²C≡CCO₂R^(b) in a suitable solvent, such as ethanol,at a suitable elevated temperature, such as 50-100° C.; and thenreducing the alkene product so formed (for example by catalytichydrogenation).

A compound of formula (I), wherein R² and R^(a) are hydrogen, Y isphenylene (optionally substituted by halogen, hydroxy, C₁₋₄ alkyl orC₁₋₄ alkoxy) and Z is CO₂R^(b), can be prepared by reacting a compoundof formula (II) with a benzyl bromide of formula BrCH₂—Y—CO₂R^(b) in thepresence of diisopropylethylamine (DIPEA), in a suitable solvent (suchas acetonitrile) and at ambient temperature (such as in the range 10-30°C.).

Alternatively, a compound of formula (I), wherein R² and R^(a) arehydrogen, Y is phenylene (optionally substituted by halogen, hydroxy,C₁₋₄ alkyl or C₁₋₄ alkoxy) and Z is CO₂R^(b), can be prepared byreacting a compound of formula (II) with a benzaldehyde of formula(O)HC—Y—CO₂R^(b) wherein R^(b) is C₁₋₄ alkyl, in the presence ofNaBH(OAc)₃ and acetic acid, in a suitable solvent (such astetrahydrofuran), optionally followed by hydrolysis of the ester group.

Compounds of formula (I) wherein R², and R^(a) are both hydrogen; Y isCH₂; and Z is CO₂R^(b) can be prepared by a Michael addition ofCH₂═CH—CO₂R^(b) on a compound of formula (II).

In another aspect the present invention provides processes for thepreparation of compounds of formula (I) or (Ia).

The compounds of the invention have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (such as CCR3) activity,and may be used in the treatment of autoimmune, inflammatory,proliferative or hyperproliferative diseases, orimmunologically-mediated diseases (including rejection of transplantedorgans or tissues and Acquired Immunodeficiency Syndrome (AIDS)).

Examples of these conditions are:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung, idiopathic interstitial pneumonia,    antitussive activity, treatment of chronic cough associated with    inflammatory conditions of the airways or iatrogenic induced cough;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behçet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, lichen    planus, phemphigus, bullous phemphigus, epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, alopecia greata, corneal ulcer or vernal    conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome    (AIDS), lupus disorders (such as lupus erythematosus or systemic    lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,    type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper    IgE syndrome, leprosy (such as lepromatous leprosy), peridontal    disease, Sezary syndrome, idiopathic thrombocytopenia pupura or    disorders of the menstrual cycle.

The compounds of formula (I) or (Ia) or a pharmaceutically acceptablesalt thereof or a solvate thereof, are also H1 antagonists (and can,therefore, be used in the treatment of allergic disorders); and may alsobe used to control a sign and/or symptom of what is commonly referred toas a cold (for example a sign and/or symptom of a common cold orinfluenza or other associated respiratory virus infection).

According to a further feature of the present invention there isprovided a method for treating a chemokine mediated disease state (suchas a CCR3 mediated disease state) in a mammal, such as man, sufferingfrom, or at risk of, said disease state, which comprises administeringto a mammal in need of such treatment a therapeutically effective amountof a compound of the formula (I) or (Ia) or a pharmaceuticallyacceptable salt thereof or a solvate thereof.

According to another feature of the present invention there is provideda method for antagonising H1 in a mammal, such as man, suffering from,or at risk of, an H1 mediated disease state, which comprisesadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of the formula (I) or (Ia) or apharmaceutically acceptable salt thereof or a solvate thereof.

According to yet another feature of the present invention there isprovided a method for treating a sign and/or symptom of what is commonlyreferred to as a cold in a mammal, such as man, suffering from, or atrisk of, said disease state, which comprises administering to a mammalin need of such treatment a therapeutically effective amount of acompound of the formula (I) or (Ia) or a pharmaceutically acceptablesalt thereof or a solvate thereof.

The invention also provides a compound of the formula (I) or (Ia), or apharmaceutically acceptable salt thereof or a solvate thereof, for usein therapy.

In another aspect the invention provides the use of a compound offormula (I) or (Ia), or a pharmaceutically acceptable salt thereof or asolvate thereof, in the manufacture of a medicament for use in therapy(for example modulating chemokine receptor activity (such as CCR3receptor activity), antagonising H1 or treating a sign and/or symptom ofwhat is commonly referred to as a cold).

The invention further provides the use of a compound of formula (I) or(Ia), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for use in the treatment of:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicarnentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung, idiopathic interstitial pneumonia,    antitussive activity, treatment of chronic cough associated with    inflammatory conditions of the airways or iatrogenic induced cough;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behcet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, lichen    planus, phemphigus, bullous phemphigus, epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, alopecia greata, corneal ulcer or vernal    conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome    (AIDS), lupus disorders (such as lupus erythematosus or systemic    lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,    type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper    IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal    disease, sezary syndrome, idiopathic thrombocytopenia pupura or    disorders of the menstrual cycle; in a mammal (for example man).

In a further aspect the invention provides a compound of formula (I) or(Ia), or a pharmaceutically acceptable salt thereof, for use in thetreatment of asthma {such as bronchial, allergic, intrinsic, extrinsicor dust asthma, particularly chronic or inveterate asthma (for examplelate asthma or airways hyper-responsiveness)}; or rhinitis {includingacute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa,hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitismedicamentosa; membranous rhinitis including croupous, fibrinous orpseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitisincluding rhinitis nervosa (hay fever) or vasomotor rhinitis}.

In a still further aspect a compound of formula (I) or (Ia), or apharmaceutically acceptable salt thereof, is useful in the treatment ofasthma.

The present invention also provides a the use of a compound of formula(I) or (Ia), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of asthma {such asbronchial, allergic, intrinsic, extrinsic or dust asthma, particularlychronic or inveterate asthma (for example late asthma or airwayshyper-responsiveness)}; or rhinitis {including acute, allergic, atrophicor chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis,rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranousrhinitis including croupous, fibrinous or pseudomembranous rhinitis orscrofulous rhinitis; seasonal rhinitis including rhinitis nervosa (hayfever) or vasomotor rhinitis}.

In order to use a compound of the invention, or a pharmaceuticallyacceptable salt thereof or solvate thereof, for the therapeutictreatment of a mammal, such as man, said ingredient is normallyformulated in accordance with standard pharmaceutical practice as apharmaceutical composition. Therefore in another aspect the presentinvention provides a pharmaceutical composition which comprises acompound of the formula (I) or (Ia), or a pharmaceutically acceptablesalt thereof or a solvate thereof (active ingredient), and apharmaceutically acceptable adjuvant, diluent or carrier.

In a further aspect the present invention provides a process for thepreparation of said composition which comprises mixing active ingredientwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill, for example, comprise from 0.05 to 99% w (percent by weight), suchas from 0.05 to 80% w, for example from 0.10 to 70% w, such as from 0.10to 50% w, of active ingredient, all percentages by weight being based ontotal composition.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by topical (such as to the lung and/or airways or to theskin), oral, rectal or parenteral administration. For these purposes thecompounds of this invention may be formulated by means known in the art.A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 0.1 mg and 1 g of active ingredient.

Each patient may receive, for example, a dose of 0.01 mgkg⁻¹ to 100mgkg⁻¹, such as in the range of 0.1 mgkg⁻¹ to 20 mgkg⁻¹, of the activeingredient administered, for example, 1 to 4 times per day.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

-   (i) when given, ¹H NMR data is quoted and is in the form of delta    values for major diagnostic protons, given in parts per million    (ppm) relative to tetramethylsilane (TMS) as an internal standard,    determined at 300 MHz or 400 MHz using perdeuterio DMSO-D6    (CD₃SOCD₃) or CDCl₃ as the solvent unless otherwise stated;-   (ii) mass spectra (MS) were run with an electron energy of 70    electron volts in the chemical ionisation (CI) mode using a direct    exposure probe; where indicated ionisation was effected by electron    impact (EI) or fast atom bombardment (FAB); where values for m/z are    given, generally only ions which indicate the parent mass are    reported, and unless otherwise stated the mass ion quoted is the    positive mass ion—(M+H)⁺;-   (iii) the title and sub-title compounds of the examples and methods    were named using the index name program from Advanced Chemistry    Development Inc;-   (iv) unless stated otherwise, reverse phase HPLC was conducted using    a Symmetry™, NovaPak™ or Xerrar™ reverse phase silica column; and

(v) the following abbreviations are used: Boc or BOC tert-butoxycarbonylDMSO dimethylsulfoxide HPLC high pressure liquid aq aqueouschromatography DIPEA Diisopropylethylamine THF tetrahydrofuran NMPN-methylpyrrolidone MeCN acetonitrile

Intermediate 14-(3,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine a)1,1-Dimethylethyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate

4-(3,4-Dichlorophenoxy)piperidine (1.27 g) was dissolved in THF (20 mL);acetic acid (0.5 mL) and 1,1-dimethylethyl4-formyl-1-piperidinecarboxylate (1.43 g) were added to the solution.The reaction mixture was stirred at room temperature for 30 min thensodium triacetoxyborohydride (1.53 g) was added and the mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto 2M sodium hydroxide solution (50 mL) and product was extracted withether. The ether was washed with brine, dried, filtered and evaporated.Crude material was purified by flash chromatography (eluting with 979:20:1 dichloromethane:methanol:aqueous ammonia) to give the subtitlecompound (2.15 g).

MS 443/445 [M+H]+(ES+)

¹H NMR δ_((CDCl3)) 1.06 (2H, ddd), 1.45 (9H, s), 1.61-1.82 (5H, m),1.92-1.98 (2H, m), 2.16-2.27 (4H, m), 2.65-2.73 (4H, m), 4.08 (2H, d),4.25 (1H, dq), 6.75 (1H, dd), 6.99 (1H, d), 7.30 (1H, d)

b) 4-(3,4-dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine

1,1-Dimethylethyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate(1.0 g) was added to a mixture of 20% TFA in dichloromethane (20 mL) andthe mixture was stirred at room temperature for 1 h. Solvent was removedby evaporation and 2M sodium hydroxide solution (25 mL) was added to theresidue. Product was extracted with ethyl acetate. The organic phase waswashed with brine, dried, filtered and evaporated to give the titlecompound (0.5 g).

MS 343/345 [M+H]⁺ (ES+)

¹H NMR δ_((CDCl3)) 1.10 (2H, qd), 1.60 (1H, qquintet), 1.73-1.83 (4H,m), 1.90-2.01 (2H, m), 2.16-2.26 (4H, m), 2.55-2.70 (4H, m), 3.09 (2H,d), 4.24 (1H, dquintet), 6.75 (1H, dd), 6.99 (1H, d), 7.27 (1H, d)

The following intermediates were prepared analogously from theappropriate aryloxy piperidine: Intermediate Name M+H ¹H NMR 24-(2,4-Dichloro-3- 357/359 δ_((CDCl3)) 1.13-1.27(2H, m), 1.57-1.70(1H,methylphenoxy)-1-(4- m), 1.76-2.00(2H, m), 2.16-2.32(4H, m),piperidinylmethyl)-piperidine 2.46(3H, s), 2.60-2.99(8H, m), 3.16(2H,d), 4.31(1H, quintet), 6.75(1H, d), 7.18(1H, d) 3 4-(4-Chloro-2- 323/325δ_((CDCl3)) 1.08-1.21(2H, m), 1.56-1.68(1H, methylphenoxy)-1-(4- m),1.73-1.86(4H, m), 1.90-1.99(2H, m), piperidinylmethyl)-piperidine2.16-2.31(7H, m), 2.57-2.69(4H, m), 3.12(2H, d), 4.23-4.31(1H, m),6.74(1H, d), 7.06(1H, dd), 7.11(1H, d) 4 4-(2,4-Dichlorophenoxy)-1-343/345 (4-piperidinylmethyl)- piperidine 5 4-(3,4-Dichloro-2- 357/359δ_((CD3OD)) 1.10-1.22(2H, m), methylphenoxy)-1-(4- 1.66-1.85(5H, m),1.94-2.04(2H, piperidinylmethyl)-piperidine m), 2.22(2H, d), 2.31(3H,s), 2.32-2.41(2H, m), 2.59-2.72(4H, m), 3.08(2H, d), 4.38-4.46(1H, m),6.91(1H, d), 7.27(1H, d)

Intermediate 6 4-(3-Chloro-4-fluoro-phenoxy)-piperidine

DEAD (0.43 mL) was added to a solution of triphenylphosphine (0.72 g),3-chloro-4-fluorophenol (0.403 g) and 4-hydroxy-piperidine-1-carboxylicacid tert-butyl ester (0.5 g) in THF at RT. The resulting mixture wasstirred overnight, HCl in dioxan (2 mL of 4M) was added and the mixturestirred at RT overnight. The mixture was then evaporated to dryness andtriethylamine (5 mL) was added. The mixture was evaporated and theresidue was dissolved in methanol (10 mL), placed onto a SCX cartridge(Varian, 10 g, SCX cartridge available from International SorbentTechnology Isolute® Flash SCX-2) and eluted: first with methanol thenwith 10% NH₃ in methanol. The basic fractions were combined andevaporated to give the product as an oil (0.6 g).

¹H NMR δ_((DMSO-D6)) 1.34-1.46 (2H, m), 1.83-1.91 (2H, m), 2.53-2.59(2H, m), 2.87-2.96 (2H, m), 3.22-3.39 (1H, m), 4.39 (1H, septet),6.92-6.98 (1H, m), 7.17-7.20 (1H, m), 7.30 (1H, t).

The following intermediate was prepared in similar manner tointermediate 6 Intermediate name M+H 74-(3,4-Dichloro-2-methylphenoxy)-piperidine 260/262

Intermediate 84-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-4-piperidinol a)1,1-Dimethylethyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-4-hydroxy-1-piperidinecarboxylate

A solution of 4-(3,4-dichlorophenoxy)-piperidine (5.2 g) and1,1-dimethylethyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (4.1 g) inethanol (50 mL) was stirred at room temperature for 18 hours and then at60° C. for 18 hours. The solvent was evaporated to leave 9.5 g of a paleyellow oil. Flash chromatography (dichloromethane then dichloromethane:7M ammonia in methanol 95:5) gave the subtitle compound (8.48 g).

MS [M+H]⁺ (ES+) 459/461

¹H NMR δ_((CDCl3)) 1.35-1.63 (4H, m), 1.46 (9H, s), 1.73-1.86 (2H, m),1.89-2.01 (2H, m), 2.34 (2H, s), 2.49-2.59 (2H, m), 2.79-2.89 (2H, m),3.07-3.24 (2H, m), 3.79-3.93 (2H, m), 4.22-4.32 (1H, m), 6.75 (1H, dd),6.99 (1H, d), 7.30 (1H, d)

b) 4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-4-piperidinol

To a solution of 1,1-dimethylethyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-4-hydroxy-1-piperidinecarboxylate(5 g) in dichloromethane (50 mL) was added trifluoroacetic acid (5 mL)and the solution was stirred for 12 hours. Sodium hydroxide solution(1M) was added to give an alkaline solution, this was then extractedthrice with dichloromethane. The pooled organic phase was subsequentlywashed with water, dried, filtered and evaporated to give the titlecompound (3.5 g).

MS [M+H]⁺ (ES+) 359/361

¹H NMR δ_((CDCl3)) 1.57-1.66 (4H, m), 1.69-1.84 (2H, m), 1.93-2.04 (2H,m), 2.36 (2H, s), 2.47-2.58 (2H, m), 2.82-2.92 (4H, m), 2.96-3.07 (2H,m), 4.32-4.41 (1H, m), 6.89 (1H, dd), 7.09 (1H, d), 7.38 (1H, d)

Intermediate 94-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1,2-cyclopentanediola) 4-(3,4-Dichlorophenoxy)-1-[1-oxo-2-(2-propenyl)₄-pentenyl]-piperidine

A solution of 4-(3,4-dichlorophenoxy)-piperidine (5.25 g) indichloromethane (80 mL) was added to a solution of EDCI (2.45 g), HOBT(1.77 g) and DMAP (0.44 g) in dichloromethane (100 mL). A solution of2-(2-propenyl)-4-pentenoic acid (1.81 g) in dichloromethane (5 mL) wasadded and the solution was stirred for 60 h. The reaction mixture waspoured onto water. The mixture was separated and the aqueous phase wasextracted twice with dichloromethane. The organic phases were washedwith brine, dried, filtered and evaporated to give an oil.Chromatography of the oil (eluting dichloromethane, then 49:1dichloromethane:methanol) gave the subtitle compound (3.40 g).

MS [M+H]⁺ (ES+) 368/342

¹H NMR δ_((CDCL3)) 5.69-5.83 (2H, m), 5.00-5.11 (4H, m), 4.46-4.52 (1H,m), 3.62-3.85 (3H, m), 3.43-3.53 (1H, m), 2.76-2.87 (1H, m), 2.37-2.47(2H, m), 2.17-2.27 (2H, m), 1.70-1.99 (4H, m), 6.77 (1H, dd), 7.01 (1H,d), 7.33 (1H, d)

b) 1-(3-Cyclopenten-1-ylcarbonyl)-4-(3,4-dichlorophenoxy)-piperidine

Nitrogen was bubbled through solution of4-(3,4-dichlorophenoxy)-1-[1-oxo-2-(2-propenyl)-4-pentenyl]-piperidine(1.45 g) in dichloromethane (20 mL) for 10 min. with sonication(cleaning bath). Grubbs' catalyst (89 mg) was added and the solution wasstirred for 16 h. Water was added and the phases were separated. Theaqueous phase was extracted twice with dichloromethane, the organicswere dried, filtered and concentrated to give the subtitle compound as agreen oil (1.60 g)

MS [M+H]⁺ (ES+) 340/342

¹H NMR δ_((CDCL3)) 4.47-4.53 (1H, m), 5.67 (2H, s), 7.33 (1H, d), 6.78(1H, dd), 7.02 (1H, d), 3.62-3.84 (3H, m), 3.44-3.52 (1H, m), 3.33 (1H,d), 2.68-2.77 (2H, m), 2.54-2.64 (2H, m), 1.88-1.99 (2H, m), 1.73-1.86(2H, m)

c) cis and trans4-(3,4-Dichlorophenoxy)-1-[(3,4-dihydroxycyclopentyl)carbonyl]-piperidine

1-(3-Cyclopenten-1-ylcarbonyl)-4-(3,4-dichlorophenoxy)-piperidine (1.45g) was dissolved in acetone (30 mL) and water (20 mL). Osmium tetroxide(1 mL of 2.5% solution in t-butanol) was added and the solution wasstirred for 5 days. The reaction mixture was poured onto a solution ofsodium metabisulfite. The mixture was extracted thrice withdichloromethane, the organic extracts were washed with brine, dried,filtered and evaporated to give an oil. Chromatography (elutingdichloromethane:methanol 24:1 to 37:3) gave the title compound as twocompounds (0.31 g and 0.71 g).

MS [M+H]⁺ (ES+) 374/376

Minor isomer ¹H NMR δ_((CDCL2)) 1.79-1.98 (6H, m), 2.12-2.22 (2H, m),3.23 (1H, tt), 3.49-3.56 (1H, m), 3.65-3.79 (3H, m), 3.93 (1H, d),3.99-4.08 (3H, m), 4.53 (1H, tt), 6.77 (1H, dd), 7.02 (1H, d), 7.34 (1H,d)

Major isomer ¹H NMR δ_((CDCL3)) 1.73-1.86 (2H, m), 1.86-2.00 (4H, m),2.07-2.16 (2H, m), 2.50-2.60 (2H, m), 3.39 (1H, tt), 3.42-3.48 (1H, m),3.61-3.78 (3H, m), 4.22-4.27 (2H, m), 4.47-4.53 (1H, m), 6.77 (1H, dd),7.01 (1H, d), 7.33 (1H, d)

d)4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1,2-cyclopentanediol

Borane solution (16 mL of 1M in THF) was added to4-(3,4-dichlorophenoxy)-1-[(3,4-dihydroxycyclopentyl)carbonyl]-piperidine(major isomer, 0.71 g) and the resulting solution was heated to refluxfor 90 min. Methanol (10 mL) was added and the mixture was heated underreflux for 1 h. The solvent was removed and the residue was loaded ontoan SCX2 cartridge with methanol. Washing with methanol followed byelution with 0.7M ammonia in methanol gave the title compound as aviscous oil containing solvent.

MS [M+H]⁺ (ES+) 360/362

The following intermediates were prepared analogously from theappropriate aryloxy piperidine as a mixture of isomers: IntermediateName M+H ¹H NMR 10 4-[[4-(2,4-Dichloro-3- 374/376 δ_((CD3OD))1.28-1.37(0.66H, m), methylphenoxy)-1- 1.37-1.48(1.34H, m),1.69-1.81(4H, piperidinyl]methyl]-1,2- m), 1.84-2.09(3H, m), 2.27(2H,d), cyclopentanediol 2.35(3H, s), 2.36-2.53(2H, m), 2.61-2.76(2H, m),3.78-3.85(0.66H, m), 3.90-3.96(1.34H, m), 4.32-4.43(1H, m), 6.85(1H, d),7.16(1H, d) 11 4-[[4-(3,4-Dichloro-2- 374/376 δ_((CD3OD))1.28-1.36(0.66H, m), methylphenoxy)-1- 1.39-1.48(1.34H, m),1.68-1.80(4H, piperidinyl]methyl]-1,2- m), 1.86-1.98(3H, m), 2.22(3H,cyclopentanediol s), 2.25(2H, d), 2.29-2.50(2H, m), 2.60-2.70(2H, m),3.78-3.84(0.66H, m), 3.89-3.95(1.34H, m), 4.29-4.38(1H, m), 6.82(1H, d),7.18(1H, d)

Intermediate 124-(3,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidineacetonitrile

4-(3,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine (0.5 g),bromoacetonitrile (0.21 g), diisopropylethylamine (0.36 mL) anddimethylformamide (3 mL) were stirred together at room temperature,under nitro gen, for 4 hours. The mixture was poured into water (50 mL),extracted into ethyl acetate (3×50 mL), washed with brine (50 mL),dried, filtered and evaporated. Flash chromatography (29:1dichloromethane: methanol) gave the title compound as a solid (363 mg).

MS [M+H]⁺ (APCI+) 382/384

¹H NMR δ_((CDCL3)) 1.24 (2H, qd), 1.45-1.55 (1H, m), 1.73-1.85 (4H, m),1.92-2.00 (2H, m), 2.19 (2H, d), 2.20-2.27 (2H, m), 2.34 (2H, td),2.63-2.71 (2H, m), 2.80 (2H, d), 3.53 (2H, s), 4.21-4.28 (1H, m), 6.75(1H, dd), 6.99 (1H, d), 7.30 (1H, d)

The following intermediates were prepared analogously from theappropriate aryloxy piperidine: Intermediate Name M+H ¹H NMR 134-[[4-(3,4-Dichloro-2- 396/398 methylphenoxy)-1- piperidinyl]methyl]-1-piperidineacetonitrile

Intermediate 144-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinepropanenitrile

4-(3,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine (0.85 g),acrylonitrile (0.24 mL), diisopropylethylamine (0.72 mL) anddimethylformamide (6 mL) were stirred together at room temperature,under nitrogen, for 24 hours. The mixture was poured into water (50 mL),extracted into ethyl acetate (3×50 mL), washed with brine (50 mL),dried, filtered and evaporated. Flash chromatography (19:1dichloromethane: methanol) gave the title compound as a solid (116 mg).

MS [M+H]⁺ (APCI+) 396/398

H NMR δ_((CD3OD)) 1.06-1.23 (2H, m), 1.40-1.53 (1H, m), 1.60-1.75 (4H,m), 1.84-1.93 (2H, m), 1.95-2.06 (2H, m), 2.11-2.17 (2H, m), 2.17-2.30(2H, m), 2.43-2.70 (6H, m), 2.76-2.95 (2H, m), 4.20-4.40 (1H, m), 6.78(1H, dd), 6.99 (1H, d), 7.28 (1H, d)

Intermediate 154-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidineethanamine

4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1piperidineacetonitrile(0.43 g) and cobalt (II) chloride (0.3 g) in methanol (20 mL) werecooled to 5° C., under nitrogen, and sodium borohydride (0.43 g) wasadded portionwise. The mixture was stirred at 5° C. for 40 minutes thenpoured into 2N aqueous sodium hydroxide solution (50 mL), extracted intoethyl acetate (3×50 mL), dried, filtered and evaporated to give thetitle compound (0.43 g).

¹H NMR δ_((CDCl3)) 1.08-1.28 (3H, m), 1.50-1.80 (6H, m), 1.88-2.02 (3H,m), 2.04-2.22 (4H, m), 2.45 (1H, s), 2.56-2.73 (3H, m), 2.89 (2H, m),3.07-3.10 (1H, d), 4.23 (1H, m), 6.74-6.76 (1H, d), 6.99 (1H, s),7.26-7.31 (1H, t)

The following intermediates were prepared analogously from theappropriate nitrile: Intermediate Name M+H ¹H NMR 164-[[4-(3,4-Dichloro-2- δ_((CDCl3)) 1.09-1.26(3H, m), 1.62-1.85(6H,methylphenoxy)-1- m), 1.88-2.01(3H, m), 2.16-2.18(2H, d),piperidinyl]methyl]-1- 2.21-2.30(2H, m), 2.32(3H, s),piperidineethanamine 2.39-2.44(1H, m), 2.58-2.71(3H, m), 2.75-2.98(2H,t), 3.03-3.16(1H, d), 4.62(1H, m), 6.70-6.73(1H, d), 7.19-7.22(1H, d) 174-[[4-(3,4-Dichlorophenoxy)- δ_((CDCl3)) 1.02-1.23(2H, m),1.40-1.83(11H, 1-piperidinyl]methyl]-1- m), 1.85-1.94(3H, m),2.08-2.20(4H, m), piperidinepropanamine 2.65(3H, m), 2.93-3.20(2H, m),4.23(1H, m), 6.73-6.76(1H, d), 6.99(1H, s), 7.26-7.31(1H, t)

Intermediate 18 1-Methylethyl 3-formyl-2-pyridinecarboxylate

1-Methylethyl 3-(hydroxymethyl)-2-pyridinecarboxylate (1.2 g) wasdissolved in dichloromethane (20 mL) and to the solution was addedDess-Martin periodinane (3.0 g). The reaction mixture was stirred, undernitrogen, at room temperature, for 1 h. Sodium thiosulphate (10 g) wasadded to a saturated aqueous solution of sodium bicarbonate (25 mL) andthis mixture was added to the reaction mixture. Ether (25 mL) was thenadded and the mixture was stirred rapidly for 5 min. The mixture wasseparated, the aqueous phase was extracted with ether (2×20 mL). 2M HCl(10 mL) was added to the combined ether extracts. The aqueous phase wasremoved, basified by careful addition of solid sodium bicarbonate andextracted with ether. This ether was dried (MgSO₄), filtered andconcentrated in vacuo to give the title compound as a colourless oil(0.87 g).

¹H NMR δ_((DMSO)) 1.35 (6H, d), 5.24 (1H, quintet), 7.80 (1H, dd), 8.31(1H, dd), 8.86 (1H, dd), 10.29 (1H, s)

Intermediate 19 Methyl 4-(bromomethyl)-3-fluoro-benzoate

Methyl 3-fluoro-4-methyl benzoate (0.97 g), N-bromosuccinimide (1.13 g)and azobisisobutyronitrile (0.02 g) were added to carbon tetrachloride(2 mL) and the mixture was heated under reflux, whilst being irradiatedwith a 100W lamp, for 6 h. The reaction mixture was concentrated invacuo and the residue was partitioned between ethyl acetate and 1 Mhydrochloric acid. The organic phase was washed with brine, dried(MgSO₄) and filtered to give a crude yellow oil which was purified byflash chromatography, eluting with 5% ethyl acetate in isohexane to givethe title compound as a colourless oil (0.63 g).

¹H NMR δ_((CDCl3)) 3.93 (3H, s), 4.52 (2H, d), 7.47 (1H, t), 7.73 (1H,dd), 7.81 (1H, dd)

Intermediate 20 Methyl 2-(bromomethyl)-5-fluoro benzoate

Prepared following the method for Intermediate 15.

¹H NMR δ_((CDCl3)) 3.95 (3H, s), 4.93 (2H, s), 7.20 (1H, ddd), 7.46 (1H,dd), 7.67 (1H, dd)

Intermediate 21 Ethyl4-[(4-hydroxy-1-piperidinyl)methyl]-α-phenyl-1-piperidineacetate a)Ethyl 4-(hydroxymethyl)-α-phenyl-1-piperidineacetate

Ethyl α-bromobenzeneacetate (2.43 g) was dissolved in acetone (20 mL). Asuspension of 4-hydroxymethylpiperidine (1.15 g) in acetone (5 mL) wasadded followed by potassium carbonate (2.60 g). The mixture was stirredfor 16 h, filtered and concentrated to an oil. Chromatography(isohexane:ethyl acetate 1:1, then 3:7) gave the subtitle compound as anoil (2.23 g).

MS [M+H]⁺ (ES+) 278

¹H NMR δ_((CDCl3)) 1.21 (3H, t), 1.32 (1H, td), 1.41 (1H, td), 1.46-1.57(1H, m), 1.63-1.69 (1H, m), 1.70-1.77 (1H, m), 1.89 (1H, td), 2.16 (1H,td), 2.76-2.81 (1H, m), 2.98-3.04 (1H, m), 3.50 (2H, d), 3.99 (1H, s),4.09-4.24 (2H, m), 7.30-7.37(3H, m), 7.42-7.46 (2H, m)

b) Ethyl 4-formyl-α-phenyl-1-piperidineacetate

DMSO (1.1 mL) was dissolved in dichloromethane (15 mL) and cooled below−60° C. Oxalyl chloride (0.9 mL) in dichloromethane (5 mL) was addeddropwise maintining the temperature below −57° C. The solution wasstirred for 15 min. then ethyl4-(hydroxymethyl)-α-phenyl-1-piperidineacetate (2.23 g) dissolved indichloromethane (6 mL) was added dropwise and the solution was stirredfor 30 min. Triethylamine (4 mL) was added and the reaction mixture wasallowed to warm to ambient temperature. Water was added, the phases wereseparated, the aqueous was extracted twice with dichloromethane and theorganic phases were washed with brine, dried, filtered and concentratedto give the subtitle compound.

MS [M+H]⁺ (ES+) 276

¹H NMR δ_((CDCl3)) 1.21 (3H, t), 1.64-1.81 (2H, m), 1.82-1.95 (1H, m),2.11 (1H, td), 2.19-2.34 (2H, m), 2.70-2.80 (2H, m), 2.81-2.90 (1H, m),4.04 (1H, s), 4.07-4.25 (2H, m), 7.30-7.38 (3H, m), 7.39-7.44 (2H, m),9.63 (1H, d)

c) Ethyl4-[(4-hydroxy-1-piperidinyl)methyl]-α-phenyl-1-piperidineacetate

4-Hydroxypiperidine (0.81 g) and ethyl4-formyl-α-phenyl-1-piperidineacetate (2.14 g) were suspended in THF (10mL). Acetic acid (0.5 mL) was added followed by sodiumtriacetoxyborohydride (1.68 g) and then THF (6 mL). The suspension wasstirred overnight, then sodium bicarbonate solution was added and themixture was stirred for 5 min. The suspension was extracted thrice withethyl acetate, the organic phases were washed with brine, dried,filtered and evaporated. Chromatography of the residue(dichloromethane:methanol:triethylamine 90:9:1) gave the subtitlecompound as an oil (2.14 g).

MS [M+H]⁺ (ES+) 361

¹H NMR δ_((CDCL3)) 1.20 (3H, td), 1.33 (2H, qd), 1.42-1.49 (1H, m),1.49-1.57 (2H, m), 1.69-1.76 (2H, m), 1.81-1.89 (3H, m), 2.00-2.12 (3H,m), 2.14 (2H, d), 2.58-2.78 (4H, m), 2.93-2.98 (1H, m), 3.61-3.70 (1H,m), 3.97 (1H, s), 4.07-4.23 (2H, m), 7.29-7.36 (3H, m), 7.41-7.45 (2H,m).

EXAMPLE 1

This Example illustrates the preparation of4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-1-piperidineaceticacid.

4-{[4-(3,4-Dichlorophenoxy)piperidin-1-yl]methyl}piperidine (0.5 g), andbenzene boronic acid (0.2 g) were dissolved in ethanol (3 mL); glyoxylicacid (0.2 mL of a 50% solution in water) was added to the solution andthe reaction mixture was heated in a microwave oven at 100° C. for 5min. The resultant solution was purified by HPLC (gradient 95%-5%aqueous ammonium acetate, 5%-95% acetonitrile) to give the titlecompound (0.1 g).

MS [M+H]⁺ (ES+) 477/479

¹H NMR δ (CDCl₃) 1.53-1.77 (4H, m), 1.79-1.94 (4H, m), 2.14-2.25 (4H,m), 2.41 (1H, t), 2.54-2.64 (2H, m), 2.75 (1H, t), 3.38 (1H, d),3.58-3.70 (2H, m), 4.15-4.23 (1H, m), 4.47 (1H, s), 6.71 (1H, dd), 6.96(1H, d), 7.25 (1H, d), 7.32-7.38 (3H, m), 7.49-7.58 (2H, m).

Examples 2-19 (see Table I below) were made using the method of Example1.

EXAMPLE 20

This Example illustrates the preparation of4-[[4-(2,5-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-1-piperidineaceticAcid

Ethyl 4-[(4-hydroxy-1-piperidinyl)methyl]-α-phenyl-1-piperidineacetate(0.135 g) was dissolved in NMP (3 mL). 1,4-Dichloro-2-fluorobenzene (0.2mL) and potassium t-butoxide (56 mg) were added and the solution washeated to 50° C. for 40 h. The solution was cooled to ambienttemperature and few drops of aqueous sodium hydroxide solution wereadded. The mixture was stirred for 60 h, then acetic acid (few drops)was added and the solvent was distilled. The residue was purified byHPLC (0.2% aqueous ammonia: acetonitrile; gradient 95:5 to 50:50) togive the title compound (21 mg).

MS [M+H]⁺ (ES+) 477/479

¹H NMR δ_((CD3OD)) 1.45 (1H, q), 1.68-1.96 (9H, m), 2.16-2.21 (2H, m),2.25-2.34 (2H, m), 2.57-2.65 (3H, m), 2.80-2.93 (2H, m), 4.29-4.36 (1H,m), 4.38-4.44 (1H, m), 6.83 (1H, dd), 7.02 (1H, d), 7.23 (1H, d),7.32-7.36 (3H, m), 7.44-7.49 (2H, m)

Example 21 (see Table I below) was made using the method of Example 20

EXAMPLE 22

This Example illustrates the preparation of methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-piperidineacetate.

4-(3,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine (0.30 g) andmethyl-α-bromobenzeneacetate (0.22 g) were dissolved in acetone (20 mL)and potassium carbonate (0.13 g) was added. The reaction mixture wasstirred at room temperature for 16 h. The suspension was filtered andthe filtrate was evaporated. The residue was chromatographed elutingwith ethyl acetate:methanol:triethylamine (20:1:0.001) to give the titlecompound (0.24 g).

MS [M+H]⁺ (ES+) 491/493

¹H NMR δ_((CD3OD)) 1.22 (1H, qd), 1.34 (2H, qd), 1.50-1.59 (1H, m), 1.66(1H, d), 1.70-1.80 (3H, m), 1.88 (1H, td), 1.93-2.02 (2H, m), 2.14 (1H,td), 2.22 (2H, d), 2.25-2.33 (1H, m), 2.65-2.73 (3H, m), 2.95-3.01 (1H,m), 3.68 (3H, s), 3.98 (1H, s), 4.37 (1H, septet), 6.87 (1H, dd), 7.08(1H, d), 7.31-7.38 (4H, m), 7.42 (2H, dd)

EXAMPLES 23 & 24

This Example illustrates the preparation of (R)-methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-piperidineacetateand (S)-methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-piperidineacetate.

Racemic methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-piperidineacetate(360 mg) was dissolved in isohexane: isopropanol (9:1) and waschromatographed on a Chiralpak AD column eluting isohexane: isopropanol(9:1) to give the 2 isomers.

First eluting isomer (50 mg); MS [M+H]⁺ (ES+) 491/493. Retention time(chiralpak AD column (4.6×250 mm), maintained at 10° C., flow rate 1mL/min 95:5 isohexane: isopropanol containing 0.1% diethylamine) 7.2minutes.

Second eluting isomer (30 mg); MS [M+H]⁺ (ES+) 491/493. Retention time(chiralpak AD column (4.6×250 mm), maintained at 10° C., flow rate 1mL/min 95:5 isohexane: isopropanol containing 0.1% diethylamine) 8.9minutes

EXAMPLE 25

This Example illustrates the preparation of(R)-4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-piperidineaceticacid.

Methyl(R)-4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-1-piperidineacetate(45 mg) was dissolved in aq. HCl (6M, 10 mL) and heated at 80° C. for 22hrs. It was dried on a rotary evaporator, redissolved in MeOH andpurified by HPLC (gradient 95%-50% aqueous ammonium acetate, 5%-50%acetonitrile) to give the title compound (14.1 mg).

MS [M+H]⁺ (ES+) 477/479

¹H NMR δ_((CD3OD+NaOD)) 1.27-1.37 (2H, m), 1.45-1.62 (2H, m), 1.72-2.06(8H, m), 2.31-2.36 (2H, m), 2.36-2.45 (2H, m), 2.72-2.80 (2H, m), 2.97(1H, t), 4.37-4.46 (2H, m), 6.88 (1H, dd), 7.09 (1H, d), 7.37 (1H, d),7.42-7.46 (3H, m), 7.54-7.58 (2H, m)

Example 26 (see Table I below) was made using the method of Example 25

EXAMPLE 27

This Example illustrates the preparation of (R)-methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-piperidineacetate

4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1,2-cyclopentanediol(Intermediate 9, major isomer, 230 mg) was dissolved in dichloromethane(5 mL). Sodium carbonate (225 mg) was added and the resulting suspensionwas cooled in ice-water. Lead tetraacetate (310 mg) was added in smallportions over 15 min. A suspension of (R)-phenylglycine methyl esterhydrochloride (129 mg) and sodium triacetoxyborohydride (300 mg) in THF(10 mL) was prepared in a separate flask. To this suspension was addedacetic acid (50 μL) and triethylamine (100 μL) then the suspension wassonicated (cleaning bath) for 5 min. 40 min after the completion of theaddition of lead tetraacetate to the diol the resulting suspension wasfiltered through a plug of cotton wool into the aminoester suspension,followed by a rinse of THF (3 mL). Additional acetic acid (50 μL) andtriethylamine (100 μL) were added to the reaction mixture which was thenstirred overnight.

Aqueous sodium bicarbonate was added to the reaction mixture which wasthen extracted thrice with ethyl acetate. The extracts were combined,washed with brine, dried, filtered and evaporated. The residue waspurified by chromatography (39:1 ethyl acetate: methanol) to give thetitle compound (157 mg).

MS [M+H]⁺ (ES+) 491/493

¹H NMR δ_((CDCl3)) 1.24 (1H, qd), 1.33 (1H, qd), 1.41-1.52 (1H, m),1.70-1.80 (3H, m), 1.85 (1H, td), 1.90-1.98 (2H, m), 2.12 (1H, td),2.16-2.25 (5H, m), 2.62-2.69 (2H, m), 2.75 (1H, d), 2.94 (1H, d), 3.69(3H, s), 4.01 (1H, s), 4.19-4.26 (1H, m), 6.74 (1H, dd), 6.98 (1H, d),7.29 (1H, d), 7.31-7.36 (3H, m), 7.40-7.44 (2H, m)

Examples 28-33 (see Table I below) were made using the method of Example27

EXAMPLE 34

This Example illustrates the preparation of(R)-4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-piperidineaceticacid dihydrochloride

(R)-Methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-phenyl-piperidineacetate(150 mg) was suspended in 6M hydrochloric acid (20 mL) and heated to 80°C. for 22 h. The crystalline solid formed was collected and dried invacuo to give the title compound (100 mg).

m. pt. 294-297 C

MS [M+H]⁺ (ES+) 477/479 ppp

¹H NMR δ_((CD3OD)) 1.43-1.59 (1H, m), 1.66 (1H, q), 1.86-2.02 (2H, m),2.05-2.29 (5H, m), 2.78-2.93 (1H, m), 2.98-3.18 (12H, m), 3.37-3.45 (2H,m), 3.61 (1H, d), 3.74-3.88 (1H, m), 4.47-4.57 (OH, m), 4.67-4.72 (1H,m), 5.00-5.12 (1H, m), 6.83-6.91 (1H, m), 7.09-7.16 (1H, m), 7.31-7.36(1H, m)

Examples 35-40 (see Table I below) were made using the method of Example25.

EXAMPLE 41

This Example illustrates the preparation of1-[4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinyl]-2,3-dihydro-1H-indene-1-carboxylicacid

4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1,2-cyclopentanediol(0.20 g) was dissolved in dichloromethane (10 mL) and sodium carbonate(0.206 g) was added. The suspension was cooled to 0° C. Leadtetraacetate (0.248 g) was added over 20 minutes. The mixture wasstirred for 40 min at 0 C.

The suspension was filtered through a plug of cotton wool into asolution of 1-amino-2,3-dihydro-1H-indene-1-carboxylic acid (0.098 g),hydrochloric acid (0.1 mL), triethylamine (0.1 mL) and methanol (10 mL).Sodium cyanoborohydride (0.052 g) was added and the reaction mixture wasstirred for 16 h at room temperature. The solvents were evaporated andthe residue was redissolved in acetonitrile/water and AcOH was added.This was purified by HPLC (5% MeCN/95% NH₄OAc aq (0.1%) gradient to 50%MeCN/50% NH₄OAc) to give title compound (93 mg).

MS [M+H]⁺ (ES+) 503/505.

H NMR (CD₃OD+NaOD) 1.17-1.27 (1H, m), 1.29-1.41 (2H, m), 1.46-1.54 (1H,m), 1.54-1.70 (3H, m), 1.83-1.93 (3H, m), 1.97-2.24 (6H, m), 2.42-2.52(2H, m), 2.55-2.65 (2H, m), 2.71-2.80 (1H, m), 2.87-3.05 (2H, m),4.22-4.31 (1H, m), 6.74-6.80 (1H, m), 6.97-7.03 (4H, m), 7.27 (1H, d),7.44 (1H, d)

EXAMPLE 42

This Example illustrates the preparation of methyl2-[(4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1-yl)methyl]benzoate

4-(3,4-Dichlorophenoxy)-1-(piperidin-4-ylmethyl)piperidine (0.5 g) wasdissolved in acetonitrile (2 mL) and to the solution was added methyl2-(bromomethyl)benzoate (0.56 g) and DIPEA (0.25 mL). The reactionmixture was stirred at room temperature overnight then concentrated byevaporation under reduced pressure. The residue was partitioned betweenethyl acetate and water, the organic phase was washed with brine, dried(MgSO₄), filtered and concentrated to give an oil. This was purified bychromatography eluting with 5% methanol in dichloromethane then by HPLC(25% MeCN/75% NH₄OAc aq (0.1%) gradient to 95% MeCN/5% NH₄OAc) to givethe title compound as an oil 0.4 g.

MS [M+H]⁺ (ES+) 491/493.

¹H NMR δ_((CDCl3)) 1.10-1.24 (2H, m), 1.46 (1H, qd), 1.63-2.05 (8H, m),2.15-2.28 (4H, m), 2.62-2.71 (2H, m), 2.76-2.82 (2H, m), 3.74 (2H, s),3.87 (3H, s), 4.23 (1H, quintet), 6.74 (1H, dd), 6.99 (1H, d), 7.25-7.32(2H, m), 7.37-7.46 (2H, m), 7.68 (1H, d).

Example 43 (see Table I below) were made using the method of Example 42.

EXAMPLE 44

This Example illustrates the preparation of methyl2-[[4-[[4-(2,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinyl]methyl]-5-fluoro-benzoate

4-(2,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidinedihydrochloride (0.26 g) was added to acetonitrile (3 mL) and treatedwith triethylamine (0.26 mL). After stirring for 5 min, methyl2-(bromomethyl)-5-fluoro benzoate (0.15 g) was added and the reactionmixture was stirred at room temperature overnight. The reaction mixturewas concentrated in vacuo and crude product was purified by flashchromatography, eluting with 2% methanol and 0.1% triethylaamine indichloromethane, giving the title compound contaminated withtriethylamine hydrochloride.

MS [M+H]⁺ (ES+) 509/511

Examples 45, 48-50 were prepared following the method of example 44.

EXAMPLE 46

This Example illustrates the preparation of1-methylethyl-3-[[4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinyl]methyl]-2-pyridinecarboxylate

4-(3,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine (0.3 g) and1-methylethyl-3-formyl-2-pyridinecarboxylate (0.17 g) were added to amixture of THF (3 mL) and acetic acid (0.5 mL). The mixture was stirredat room temperature for 5 min then sodium triacetoxyborohydride (0.28 g)was added. The mixture was stirred overnight then poured into asaturated solution of sodium bicarbonate. The product was extracted withethyl acetate, the organic phase was washed with brine, dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by flashchromatography, eluting with 3% methanol and 0.1% triethylamine indichloromethane, giving the title compound as a clear oil (0.24 g).

¹H NMR δ_((CD3OD)) 1.13-1.28 (2H, m), 1.43 (6H, d), 1.50-1.65 (1H, m),1.69-1.83 (4H, m), 1.96-2.11 (4H, m), 2.23 (2H, d), 2.27-2.37 (2H, m),2.67-2.84 (4H, m), 3.72 (2H, s), 4.35-4.45 (1H, m), 5.26 (1H, t), 6.90(1H, dd), 7.11 (1H, d), 7.39 (1H, d), 7.52 (1H, dd), 7.93 (1H, dd), 8.49(1H, dd)

Examples 47, 60-66 (Table I below) were prepared following the method ofExample 46.

EXAMPLES 51-59

Examples 51-59 (Table I below) were made from Examples 42-50 by themethods of Example 77 (LiOH, Examples 51, 53, 54, 57, 58, 59), Example25 (HCl, Examples 55, 56) or Example 90 (KOTMS, Example 52).

EXAMPLE 67

This Example illustrates the preparation of methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidineacetate

To a stirred solution of4-(3,4-dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine (0.23 g) andDIPEA (0.164 mL) in DMF at RT was added methyl bromoacetate (0.076 mL).The reaction was heated at 60° C. for 16 h. Saturated sodium bicarbonatesolution (30 mL) was then added to the cooled solution and the productwas extracted into ethyl acetate (3×20 mL). The combined organics werewashed with brine (10 mL) and then dried, filtered and evaporated toleave a colourless oil (0.135 g).

MS [M+H]⁺ (ES+) 415/417

Examples 68-72 (see Table I) were prepared analogously to Example 67from the appropriate amine.

EXAMPLE 73

This Example illustrates the preparation of methyl(2R)-2-(4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1-yl)propanoate

Diethyl ether (10 mL) and dimethylformamide (2 mL) were added to4-(3,4-dichlorophenoxy)-1-(piperidin-4-ylmethyl)piperidine (0.32 g) andthe mixture was sonicated (cleaning bath) until it became clear. Methyl(2S)-2-bromopropanoate (0.16 g) and triethylamine (0.6 mL) were addedand the mixture was stirred at room temperature overnight. The reactionmixture was poured into water and was extracted with diethyl ether. Thediethyl ether was washed with brine, dried (MgSO₄), filtered andconcentrated under reduced pressure to give an oil. Crude product waspurified by chromatography, eluting with 95:5:0.1dichloromethane:methanol:aqueous ammonia to give the title compound asan oil (0.25 g).

MS [M+H]⁺ (ES+) 429/431

Examples 74-76 (see Table I) were prepared analogously to Example 73.

EXAMPLE 77

This Example illustrates the preparation of4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidineaceticacid.

Methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidineacetate(0.135 g) and lithium hydroxide (0.136 g) in 3:1 methanol/water (2 mL)was stirred at RT for 16 h. The reaction mixture was acidified to pH 4with acetic acid and purified by HPLC (10% MeCN/90% NH₄OAc aq (0.1%)gradient to 70% MeCN/30% NH₄OAc) to provide the title compound as awhite solid (0.030 g).

MS [M+H]⁺ (ES+) 401/403.

¹H NMR δ_((CD3OD)) 1.52 (2H, qd), 1.72-1.92 (3H, m), 1.98-2.09 (4H, m),2.34 (2H, d), 2.38-2.45 (2H, m), 2.72-2.83 (2H, m), 3.01 (2H, td),3.56-3.67 (4H, m), 4.35-4.49 (1H, m), 6.90 (1H, dd), 7.11 (1H, d), 7.39(1H, d).

Examples 78-86 (see Table I) were prepared analogously to Example 77from the appropriate ester.

EXAMPLE 87

This Example illustrates the preparation of methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α,α-dimethyl-1-piperidinepropanoate

To a stirred solution of4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidine (0.175 g)and 2,2-dimethyl-3-oxopropanoic acid methyl ester (80 mg) in THF (0.5mL) was added sodium triacetoxyborohydride (162 mg) and acetic acid(0.041 mL). The reaction mixture was stirred at room temperatureovernight. Saturated sodium bicarbonate solution (30 mL) was added andthe product was extracted into ethyl acetate (3×20 mL). The combinedorganics were washed with brine (10 mL) and dried (MgSO₄), filtered andevaporated to leave an oil (0.17 g). A portion (0.080 g) was purified byHPLC (5% MeCN/95% NH₄OAc aq (0.1%) gradient to 5% MeCN/95% NH₄OAc) togive the title compound as an oil (0.012 g).

MS [M+H]⁺ (ES+) 457/459.

¹H NMR δ_((CDCl3)) 1.15 (6H, s), 1.16 (1H, qd), 1.34-1.45 (1H, m),1.58-1.62 (2H, m), 1.62-1.66 (2H, m), 1.71-1.82 (2H, m), 1.90-2.00 (2H,m), 2.07-2.16 (3H, m), 2.16-2.26 (2H, m), 2.45 (2H, s), 2.60-2.70 (2H,m), 2.70-2.77 (2H, m), 3.65 (3H, s), 4.18-4.27 (1H, m), 6.74 (1H, dd),6.99 (1H, d), 7.30 (1H, d).

Examples 88 & 89 (see Table 1) were prepared analogously to Example 87from the appropriate amines.

EXAMPLE 90

This Example illustrates the preparation of4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α,α-dimethyl-1-piperidinepropanoic acid.

To a stirred solution of methyl4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α,α-dimethyl-1-piperidinepropanoate (0.080 g) in THF (1 mL) at RT was added potassiumtrimethylsilanolate (27 mg). After 16 h the reaction mixture wasincomplete and further potassium trimethylsilanolate (27 mg) was added.After a further 1 h the reaction solvent was evaporated and the residuewas redissolved in acetonitrile and purified by HPLC (5% MeCN/95% NH₄OAcaq (0.1%) gradient to 60% MeCN/40% NH₄OAc) to give the title compound(0.036 g).

MS [M+H]⁺ (ES+) 443/445.

¹H NMR δ_((CD3OD)) 1.22 (6H, s), 1.47 (2H, q), 1.68-1.81 (2H, m),1.79-1.88 (1H, m), 1.93-2.05 (4H, m), 2.27 (2H, d), 2.33 (2H, t),2.67-2.76 (2H, m), 2.95-3.02 (2H, m), 3.04 (2H, s), 3.45-3.52 (2H, m),4.33-4.42 (1H, m), 6.87 (1H, dd), 7.08 (1H, d), 7.36 (1H, d).

Example 91 & 92 (Table I) were prepared analogously to Example 90 fromthe appropriate esters

EXAMPLE 93

This Example illustrates the preparation of4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidine propanoicacid dihydrochloride

To a stirred solution of4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidine (0.175 g) inisopropanol (0.4 mL) at RT was added acrylic acid (0.038 mL). After 16 hthe reaction mixture was purified by HPLC (5% MeCN/95% NH₄OAc aq (0.1%)gradient to 50% MeCN/50% NH₄OAc). Treatment of the product with 2 M HClat 40° C. for 15 min followed by evaporation left a yellow solid. Thiswas triturated with diethyl ether (3 mL) and the residual solid waspartially dissolved in 4:1 dichloromethane/methanol. The supernatant wasevaporated to provide the title compound as a solid (0.014 g).

MS [M+H]⁺ (ES+) 415/417.

¹H NMR δ_((D2O)) 1.63 (2H, qd), 1.91-2.05 (1H, m), 2.09-2.21 (2H, m),2.26 (2H, d), 2.29-2.36 (1H, m), 2.40 (1H, d), 2.87 (2H, t), 3.08 (2H,t), 3.14-3.22 (2H, m), 3.29-3.40 (2H, m), 3.44 (2H, t), 3.52 (1H, d),3.64-3.79 (3H, m), 4.61-4.70 (1H, m), 6.96-7.03 (1H, m), 7.24-7.29 (1H,m), 7.50 (1H, d).

EXAMPLE 94

This Example illustrates the preparation of4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinebutanoicacid.

4-(3,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine (0.20 g) andmethyl 4-bromo-butanoate (0.10 g) were dissolved in acetone (20 mL) andpotassium carbonate (0.08 g) was added. The reaction mixture was stirredfor 16 h at room temperature. The reaction mixture was filtered and thesolvents were evaporated to give the title compound (18 mg).

MS [M+H]⁺ (ES+) 443/445

Example 95 & 96 (Table I) wre prepared analogously to Example 94 fromthe appropriate halo esters.

Examples 97-99 (Table I) were prepared from the appropriate esters bythe method of Example 25.

EXAMPLE 100

This Example illustrates the preparation of4-(3,4-dichlorophenoxy)-1-[[1-(2H-tetrazol-5-ylmethyl)-4-piperidinyl]methyl]-piperidine

4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidineacetonitrile(0.26 g), azidotrimethylsilane (0.5 mL), dibutyltin oxide (0.17 g) andtoluene (10 mL) were heated together at 110° C., in a sealed tube, for20 hours, cooled and evaporated. The residue was dissolved in methanol,and filtered through reverse-phase silica to remove the tin by-products.The product was further purified by reverse-phase HPLC (25% MeCN/75%NH₄OAc aq (0.1%) gradient to 95% MeCN/5% NH₄OAc). This gave the titlecompound as a solid (0.24 g).

MS [M+H]⁺ (APCI+) 425/427.

¹H NMRδ_((CD3OD)) 1.16-1.38 (2H, m), 1.71-1.84 (5H, m), 1.91-2.05 (2H,m), 2.37-2.49 (2H, m), 2.50-2.69 (4H, m), 2.79-2.98 (2H, m), 3.20-3.25(2H, m), 4.12 (2H, s), 4.33-4.46 (1H, m), 6.81 (1H, dd), 7.04 (1H, d),7.29 (1H, d)

Example 101 (Table I) was prepared analogously to Example 100 from theappropriate nitrile.

EXAMPLE 102

This Example illustrates the preparation ofN-[2-[4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinyl]ethyl]-1,1,1-trifluoro-methanesulfonamide4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidineethanamine(0.28 g) in dichloromethane (25 mL) was cooled to −78° C. undernitrogen, and triflic anhydride 0.35 mL) was added dropwise. After 5minutes the reaction was quenched with excess aqueous ammonia solution,warmed to room temperature, and evaporated. The product was purified byreverse-phase HPLC (25% MeCN/75% NH₄OAc aq (0.1%) gradient to 95%MeCN/5% NH₄OAc). This gave the title compound as a solid (0.08 g).

MS [M+H]⁺ (APCI+) 518/520.

¹H NMRδ_((CD3OD)) 1.25 (2H, dd), 1.54-1.72 (3H, m), 1.79 (2H, d),1.85-1.95 (2H, m), 2.18 (2H, d), 2.25 (2H, t), 2.35 (2H, td), 2.57-2.74(4H, m), 3.11 (2H, d), 3.25 (2H, t), 4.19-4.43 (1H, m), 6.79 (1H, dd),7.00 (1H, d), 7.28 (1H, d)

Examples 103 and 104 (Table I) were prepared analogously to Example 102from the appropriate amines. TABLE I Example Name M+H ¹H NMR 24-[[4-(2,4-Dichloro-3- 491/493 δ_((CDCl3)) 1.56-1.72(3H, m),1.83-1.97(6H, m), 2.23(2H, d), 2.30-2.39(2H, methylphenoxy)-1- m),2.45(3H, s), 2.50-2.52(1H, m), 2.62-2.68(2H, m), 2.76-2.84(1H, m),piperidinyl]methyl]-α-phenyl-1- 3.39(1H, d), 3.71(2H, d), 4.32(1H, s),4.57(1H, s), 6.71(1H, d), 7.17(1H, d), piperidineacetic acid7.36-7.38(3H, m), 7.53-7.56(2H, m) 3 4-[[4-(3,4-Dichlorophenoxy)-1-495/497 δ_((CDCl3)) 1.56-1.78(5H, m), 1.84-1.98(4H, m), 2.18-2.32(4H,m), 2.37-2.53(1H, piperidinyl]methyl]-α-(4- m), 2.57-2.67(2H, m),2.72-2.84(1H, m), 3.36-3.43(1H, m), fluorophenyl)-1-piperidineacetic3.64-3.72(1H, m), 4.19-4.26(1H, m), 4.54(1H, s), 6.72(1H, dd), 6.96(1H,acid d), 7.07(2H, t), 7.24-7.32(1H, m), 7.55(2H, dd) 44-[[4-(3,4-Dichlorophenoxy)-1- 507/509 δ_((CDCl3)) 1.55-1.79(5H, m),1.86-2.00(4H, m), 2.16-2.27(4H, m), 2.39-2.74(4H,piperidinyl]methyl]-α-(2- m), 2.87(1H, t), 3.37(1H, d), 3.69-3.78(1H,m), 3.87(3H, s), 4.18-4.26(1H, methoxyphenyl)-1- m), 5.03(1H, s),6.72(1H, dd), 6.91-7.03(3H, m), 7.25-7.31(1H, piperidineacetic acid m),7.37(1H, t), 7.51(1H, d) 5 4-[[4-(3,4-Dichlorophenoxy)-1- 491/493δ_((CDCl3)) 1.47-1.75(4H, m), 1.80-1.95(5H, m), 2.12-2.23(4H, m),2.43-2.66(6H, piperidinyl]methyl]-α-(2- m), 2.76-2.90(1H, m), 3.39(1H,d), 3.49(1H, s), 3.84-3.96(1H, methylphenyl)-1-piperidineacetic m),4.14-4.25(1H, m), 4.76(1H, s), 6.72(1H, dd), 6.96(1H, d), 7.16-7.32 acid(4H, m), 7.78(1H, d) 6 4-[[4-(3,4-Dichlorophenoxy)-1- 491/493δ_((CDCl3)) 1.55-1.79(5H, m), 1.81-1.96(4H, m), 2.14-2.25(4H, m),2.35(3H, piperidinyl]methyl]-α-(4- s), 2.43-2.73(4H, m), 2.76-2.87(1H,m), 3.47(1H, d), 3.68-3.77(1H, m), methylphenyl)-1-piperidineacetic4.15-4.25(1H, m), 4.54(1H, s), 6.72(1H, dd), 6.96(1H, d), 7.18(2H, d),7.26-7.31(1H, acid m), 7.42(2H, d) 7 4-[[4-(2,4-Dichloro-3- 521/523δ_((CDCl3)) 1.55-1.68(2H, m), 1.74-2.00(5H, m), 2.16-2.28(4H, m),2.45(3H, methylphenoxy)-1- s), 2.57-2.90(6H, m), 3.41(1H, d),3.66-3.77(1H, m), 3.87(3H, s), 4.24-4.35(1H, piperidinyl]methyl]-α-(2-m), 5.09(1H, s), 6.72(1H, d), 6.92-7.02(2H, m), 7.17(1H, d), 7.36(1H,methoxyphenyl)-1- dd), 7.53(1H, d) piperidineacetic acid 84-[[4-(2,4-Dichloro-3- 505/507 δ_((CDCl3)) 1.73-1.96(8H, m),2.14-2.28(5H, m), 2.45(3H, s), 2.53(3H, s), 2.57-2.66(4H,methylphenoxy)-1- m), 2.75-2.86(1H, m), 3.36(1H, d), 3.80-3.91(1H, m),4.24-4.32(1H, piperidinyl]methyl]-α-(2- m), 4.73(1H, s), 6.71(1H, d),7.14-7.24(4H, m), 7.77(1H, d) methylphenyl)-1-piperidineacetic acid 94-[[4-(2,4-Dichloro-3- 505/507 δ_((CDCl3)) 1.55-1.94(9H, m),2.14-2.27(4H, m), 2.35(3H, s), 2.45(3H, s), 2.52-2.82(5H,methylphenoxy)-1- m), 3.46(1H, d), 3.64-3.73(1H, m), 4.24-4.32(1H, m),4.47(1H, piperidinyl]methyl]-α-(4- s), 6.71(1H, d), 7.17(3H, d),7.43(2H, d) methylphenyl)-1-piperidineacetic acid 10 4-[[4-(4-Chloro-2-487/489 δ_((CDCl3)) 1.58-1.65(2H, m), 1.70-1.80(4H, m), 1.85-1.95(4H,m), 2.15-2.26(7H, methylphenoxy)-1- m), 2.46-2.74(3H, m), 2.80-2.91(1H,m), 3.42(1H, d), 3.68-3.77 piperidinyl]methyl]-α-(2- (1H, m), 3.87(3H,s), 4.19-4.28(1H, m), 5.09(1H, s), 6.70(1H, d), 6.91-7.11(4H,methoxyphenyl)-1- m), 7.36(1H, dd), 7.53(1H, d) piperidineacetic acid 114-[[4-(4-Chloro-2- 471/473 δ_((CDCl3)) 1.48-1.95(11H, m), 2.13(3H, s),2.25(2H, t), 2.46-2.90(8H, m), methylphenoxy)-1- 3.36(1H, d),3.83-3.93(1H, m), 4.19-4.28(1H, m), 4.78(1H, s), 6.70(1H,piperidinyl]methyl]-α-(2- d), 7.02-7.11(2H, m), 7.15-7.25(3H, m),7.74(1H, d) methylphenyl)-1-piperidineacetic acid 12α-[4-[[4-(3,4-Dichlorophenoxy)- 539/541 δ_((CDCl3)) 1.48-2.80(19H, m),3.27-3.35(1H, m), 3.51(3H, s), 3.99(3H, s), 1-piperidinyl]methyl]-1-4.29-4.37(1H, m), 4.55(1H, s), 6.73(1H, dd), 6.98(1H, d), 7.31(1H, d),8.06(1H, piperidinyl]-2,4-dimethoxy-5- s) pyrimidineacetic acid 134-[[4-(4-Chloro-2- 471/473 δ_((CDCl3)) 1.56-1.79(5H, m), 1.83-1.94(4H,m), 2.13-2.27(7H, m), 2.35(3H, methylphenoxy)-1- s), 2.44-2.95(5H, m),3.48(1H, d), 3.71(1H, d), 4.19-4.28(1H, m), 4.50(1H,piperidinyl]methyl]-α-(4- s), 6.70(1H, d), 7.03-7.11(2H, m), 7.18(2H,d), 7.43(2H, d) methylphenyl)-1-piperidineacetic acid 14α-[3-(Acetylamino)phenyl]-4-[[4- 534/536 δ_((CDCl3)) 1.46-1.64(2H, m),1.68-1.83(3H, m), 1.87-1.97(2H, m), 2.05-2.25(7H,(3,4-dichlorophenoxy)-1- m), 2.36-2.77(8H, m), 3.33-3.68(2H, m),4.22(1H, s), 4.41(1H, piperidinyl]methyl]-1- s), 6.73(1H, dd),6.96-7.02(2H, m), 7.22-7.33(2H, m), 7.49(1H, s), 8.09(1H,piperidineacetic acid d) 15 4-[[4-(2,4-Dichloro-3- 509/511 δ_((CDCl3))1.54-2.47(18H, m), 2.61-2.72(2H, m), 3.28-3.35(1H, m), 3.54-3.61(1H,methylphenoxy)-1- m), 4.29-4.42(2H, m), 6.71(1H, d), 7.05(2H, t),7.17(1H, d), 7.54(2H, piperidinyl]methyl]-α-(4- dd)fluorophenyl)-1-piperidineacetic acid 16 4-[[4-(2,4-Dichlorophenoxy)-1-477/479 δ_((CD3OD)) 1.48-1.61(2H, m), 1.75-1.89(4H, m), 1.90-2.04(4H,m), 2.28(2H, piperidinyl]methyl]-α-phenyl-1- d), 2.33-2.41(2H, m),2.67-2.77(3H, m), 2.96(2H, t), 4.37-4.50(2H, m), piperidineacetic acid7.07(1H, d), 7.22(1H, dd), 7.39(1H, d), 7.42-7.46(3H, m), 7.54-7.58(2H,m) 17 4-[[4-(3,4-Dichlorophenoxy)-1- 493/495 δ_((CD3OD)) 1.64-1.82(4H,m), 1.85-2.03(3H, m), 2.40(2H, s), 2.49-2.57(2H,piperidinyl]methyl]-4-hydroxy-α- m), 2.81-2.90(3H, m), 2.98-3.16(2H, m),3.51-3.72(2H, m), 4.32-4.39(1H, phenyl-1-piperidineacetic acid m),4.52(1H, s), 6.87(1H, dd), 7.08(1H, d), 7.37(1H, d), 7.42-7.47(3H, m),7.55-7.60(2H, m) 18 4-[[4-(3,4-Dichlorophenoxy)-1- 507/509 δ_((CD3OD))1.64-1.81(4H, m), 1.82-2.02(4H, m), 2.36(3H, s), 2.40(2H, s),piperidinyl]methyl]-4-hydroxy-α- 2.49-2.57(2H, m), 2.81-2.89(2H, m),2.92-3.06(2H, m), 3.62-3.75(2H, (4-methylphenyl)-1- m), 4.32-4.39(1H,m), 4.47(1H, s), 6.87(1H, dd), 7.08(1H, d), 7.26(2H, d),piperidineacetic acid 7.36(1H, d), 7.44(2H, d) 194-[[4-(3,4-Dichlorophenoxy)-1- 523/525 δ_((CD3OD)) 1.65-1.80(4H, m),1.93-2.04(4H, m), 2.40(2H, s), 2.48-2.57(2H,piperidinyl]methyl]-4-hydroxy-α- m), 2.81-2.89(2H, m), 2.94-3.06(2H, m),3.67-3.77(2H, m), 3.91(3H, s), (2-methoxyphenyl)-1- 4.32-4.39(1H, m),4.98(1H, s), 6.87(1H, dd), 7.03(1H, td), 7.08(1H, d), piperidineaceticacid 7.09-7.12(1H, m), 7.36(1H, d), 7.41-7.46(1H, m), 7.53(1H, dd) 214-[[4-(2,6-Dichlorophenoxy)-1- 477/479 δ_((CD3OD)) 1.37-1.53(2H, m),1.67-1.80(4H, m), 1.81-1.96(3H, m), 2.19(2H,piperidinyl]methyl]-α-phenyl-1- d), 2.24-2.35(2H, m), 2.56-2.74(3H, m),2.80-2.92(2H, m), 3.61-3.80(1H, piperidineacetic acid m), 4.28-4.35(1H,m), 4.38-4.46(1H, m), 6.94(1H, dd), 6.99(1H, dd), 7.10(1H, t),7.31-7.37(3H, m), 7.43-7.50(2H, m) 26 (S)-4-[[4-(3,4-Dichlorophenoxy)-477/479 δ_((CD3OD+NaOD)) 1.25-1.38(2H, m), 1.44-1.62(2H, m),1.68-2.06(8H, m), 1-piperidinyl]methyl]-α-phenyl- 2.27-2.41(4H, m),2.69-2.78(2H, m), 2.97(1H, t), 4.35-4.47(2H, m), 6.87(1H,piperidineacetic acid dd), 7.09(1H, d), 7.37(1H, d), 7.44(3H, t),7.54-7.59(2H, m) 28 Methyl 4-[[4-(2,4-dichloro-3- 505/507methylphenoxy)-1- piperidinyl]methyl]-α-phenyl-1-piperidineacetate(α¹R)- 29 (α¹S)-1,1-Dimethylethyl 4-[[4- 547/549(2,4-dichloro-3-methylphenoxy)- 1-piperidinyl]methyl]-α-phenyl-1-piperidineacetate 30 (α¹R)-Methyl 4-[[4-(3,4- 505/507dichloro-2-methylphenoxy)-1- piperidinyl]methyl]-α-phenyl-1-piperidineacetate 31 (α¹R)-Methyl 4-[[4-(3,4- 505/507dichloro-2-methylphenoxy)-1- piperidinyl]methyl]-α-phenyl-1-piperidineacetate 32 Methyl(S)-4-[[4-(3,4- 457/459 dichlorophenoxy)-1-piperidinyl]methyl]-α-(1- methylethyl)-1-piperidineacetate 331,1-Dimethylethyl 4-[[4-(3,4- 485/487 dichlorophenoxy)-1-piperidinyl]methyl]-α,α- dimethyl-1-piperidineacetate 35(α¹R)-4-[[4-(2,4-Dichloro-3- 491/493 δ_((CD3OD)) 1.43-1.63(2H, m),1.78-1.89(4H, m), 1.91-2.05(3H, m), 2.15(1H, methylphenoxy)-1- s),2.32(2H, d), 2.38-2.48(5H, m), 2.69-2.80(3H, m), 2.91-3.05(2H, m),piperidinyl]methyl]-α-phenyl-1- 4.40-4.52(2H, m), 6.94(1H, d), 7.25(1H,d), 7.43-7.45(3H, m), 7.55-7.58(2H, piperidineacetic acid m) 36(α¹S)-4-[[4-(2,4-Dichloro-3- 491/493 δ_((CD3OD)) 1.42-1.62(2H, m),1.77-1.90(4H, m), 1.90-2.05(4H, m), 2.30(2H, methylphenoxy)-1- d),2.35-2.45(5H, m), 2.72(3H, t), 2.97(2H, t), 4.40-4.49(2H, m), 6.93(1H,piperidinyl]methyl]-α-phenyl-1- d), 7.25(1H, d), 7.42-7.46(3H, m),7.53-7.59(2H, m) piperidineacetic acid 37 (α¹R)-4-[[4-(3,4-Dichloro-2-491/493 δ_((CD3OD)) 1.43-1.67(2H, m), 1.76-1.94(4H, m), 1.95-2.10(4H,m), 2.30-2.37(5H, methylphenoxy)-1- m), 2.45(2H, t), 2.75(3H, t),3.01(2H, t), 4.41-4.52(2H, m), 6.93(1H, piperidinyl]methyl]-α-phenyl-1-d), 7.30(1H, d), 7.47(3H, dd), 7.59(2H, q) piperidineacetic acid 38(α¹S)-4-[[4-(3,4-Dichloro-2- 491/493 δ_((CD3OD)) 1.30-1.54(2H, m),1.65-1.81(4H, m), 1.81-1.98(4H, m), 2.19-2.25 methylphenoxy)-1- (5H, m),2.28-2.39(2H, m), 2.57-2.70(3H, m), 2.82-2.98(2H, m),piperidinyl]methyl]-α-phenyl-1- 4.29-4.40(2H, m), 6.81(1H, d), 7.18(1H,d), 7.32-7.39(3H, m), 7.43-7.51(2H, piperidineacetic acid m) 39(S)-4-[[4-(3,4-Dichlorophenoxy)- 443/445 δ_((CD3OD+NaOD)) 1.02(3H, d),1.14(3H, d), 1.26-1.38(3H, m), 1.42-1.64(2H, 1-piperidinyl]methyl]-α-(1-m), 1.73-1.85(2H, m), 1.98-2.07(4H, m), 2.28-2.39(2H, m), 2.40-2.49(2H,methylethyl)-1-piperidineacetic m), 2.75-2.84(2H, m), 2.97-3.04(2H, m),3.46-3.58(2H, m), 4.39-4.46 acid (1H, m), 6.89(1H, dd), 7.10(1H, d),7.38(1H, d) 40 4-[[4-(3,4-Dichlorophenoxy)-1- 429/431 δ_((CD3OD+NaOD))1.17-1.55(8H, m), 1.61-1.77(2H, m), 1.77-2.01(7H, m),piperidinyl]methyl]-α,α- 2.23-2.40(3H, m), 2.63-2.75(2H, m), 2.88(2H,t), 3.31-3.42(1H, m), 4.28-4.39(1H, dimethyl-1-piperidineacetic acid m),6.79(1H, dd), 7.01(1H, d), 7.28(1H, d) 43 methyl 2-[(4-{[4-(2,4- 491/493Dichlorophenoxy)piperidin-1- yl]methyl}piperidin-1- yl)methyl]benzoate51 2-[(4-{[4-(3,4- 477/479 δ_((CD3OD)) 1.30-1.46(2H, m), 1.70-1.83(3H,m), 1.95-2.11(4H, m), 2.25-2.41(4H, dichlorophenoxy)piperidin-1- m),2.69-2.79(2H, m), 2.94(2H, t), 3.31-3.41(2H, m), 4.26(2H,yl]methyl}piperidin-1- s), 4.41(1H, dt), 6.90(1H, dd), 7.11(1H, d),7.39(2H, d), 7.51(2H, dtd), 7.97(1H, yl)methyl]benzoic acid dd) 522-[[4-[[4-(2,4-Dichlorophenoxy)- 477/479 δ_((CD3OD+NaOD)) 1.19-1.34(2H,m), 1.47-1.61(1H, m), 1.69-1.76(2H, m), 1-piperidinyl]methyl]-1-1.76-1.86(2H, m), 1.93-2.08(4H, m), 2.22(2H, d), 2.29-2.37(2H, m),2.64-2.72(2H, piperidinyl]methyl]-benzoic acid m), 2.89-2.95(2H, m),3.83(2H, s), 4.41-4.48(1H, m), 7.07(1H, d), 7.16-7.28(3H, m), 7.38(1H,d), 7.41-7.45(2H, m) 57 2-[[4-[[4-(3,4-Dichlorophenoxy)- 495/497δ_((CD3OD)) 1.24-1.40(2H, m), 1.66-1.77(2H, m), 1.81-1.99(5H, m),2.34(2H, 1-piperidinyl]methyl]-1- d), 2.43(2H, t), 2.71-2.79(2H, m),2.86(2H, t), 3.22-3.29(2H, m), 4.15 piperidinyl]methyl]-5-fluoro- (2H,s), 4.31-4.39(1H, m), 6.80(1H, dd), 7.01(1H, d), 7.11(1H, td), 7.29(1H,benzoic acid d), 7.31(1H, dd), 7.56(1H, dd) 584-[[4-[[4-(2,4-Dichlorophenoxy)- 495/497 δ_((CD3OD)) 1.30-1.49(2H, m),1.82-1.96(3H, m), 2.00-2.07(2H, m), 2.11-2.22(2H,1-piperidinyl]methyl]-1- m), 2.47-2.58(2H, m), 2.69(2H, d),2.86-2.97(2H, m), 3.03-3.22(4H, piperidinyl]methyl]-3-fluoro- m),3.95(2H, s), 4.60-4.69(1H, m), 7.14(1H, d), 7.28(1H, dd), 7.44-7.51(2H,benzoic acid m), 7.68(1H, dd), 7.78(1H, dd) 592-[[4-[[4-(3,4-Dichlorophenoxy)- 468/470 δ_((CD3OD)) 1.20-1.32(2H, m),1.77(3H, d), 1.92-2.00(2H, m), 2.08-2.15(4H, 1-piperidinyl]methyl]-1-m), 2.81(2H, d), 2.90(2H, d), 3.11-3.22(4H, m), 3.64(2H, s), 4.55(1H,s), piperidinyl]methyl]-4- 6.85(1H, dd), 7.10(1H, d), 7.31(1H, d),8.06(1H, s) oxazolecarboxylic acid, 60 4-[[4-[[4-(3,4-Dichlorophenoxy)-477/479 δ_((CD3OD)) 1.29(2H, q), 1.70-1.83(5H, m), 1.93-2.01(2H, m),2.40(2H, d), 1-piperidinyl]methyl]-1- 2.44-2.58(4H, m), 2.82(2H, tt),3.12(2H, d), 3.88(2H, s), 4.34-4.43(1H, piperidinyl]methyl]-benzoic acidm), 6.81(1H, dd), 7.03(1H, d), 7.29(1H, d), 7.33(2H, d), 7.87(2H, d) 613-[[4-[[4-(3,4-Dichlorophenoxy)- 477/479 δ_((CD3OD)) 1.25-1.41(2H, m),1.66-1.78(3H, m), 1.82-1.99(4H, m), 2.32(2H, 1-piperidinyl]methyl]-1-d), 2.37-2.47(2H, m), 2.59-2.79(4H, m), 3.25(2H, s), 4.00(2H, s),4.30-4.39(1H, piperidinyl]methyl]-benzoic acid m), 6.79(1H, dd),7.01(1H, d), 7.28(1H, d), 7.31-7.42(2H, m), 7.87-7.92(2H, m) 622-[[4-[[4-(2,4-Dichloro-3- 491/493 δ_((CD3OD)) 1.31-1.50(2H, m),1.81-1.93(3H, m), 1.96-2.11(4H, m), 2.39(2H, methylphenoxy)-1- d),2.45-2.55(5H, m), 2.77-2.85(2H, m), 2.90-3.03(2H, m), 3.34-3.40(2H,piperidinyl]methyl]-1- m), 4.27(2H, s), 4.46-4.54(1H, m), 6.97(1H, d),7.28(1H, d), 7.38-7.41(1H, piperidinyl]methyl]-benzoic acid m), 7.51(2H,dtd), 7.98(1H, dd) 63 2-[[4-[[4-(3,4-Dichloro-2- 491/493 δ_((CD3OD))1.26-1.42(2H, m), 1.74-1.85(3H, m), 1.92-2.09(4H, m), 2.24-2.32(2H,methylphenoxy)-1- m), 2.30(3H, s), 2.38(2H, t), 2.69(2H, t), 2.91(2H,t), 3.30-3.39(2H, piperidinyl]methyl]-1- m), 4.19-4.26(2H, m),4.37-4.47(1H, m), 6.90(1H, d), 7.26(1H, d), piperidinyl]methyl]-benzoicacid 7.36(1H, d), 7.48(2H, quintetd), 7.95(1H, d) 64[2-[[4-[[4-(2,4-Dichloro-3- 521/523 δ_((CD3OD)) 1.46-1.63(2H, m),1.69-1.95(7H, m), 2.23-2.29(2H, m), 2.31-2.40 methylphenoxy)-1- (5H, m),2.63-2.73(2H, m), 2.79-2.91(2H, m), 3.35(2H, d), 4.11(2H,piperidinyl]methyl]-1- s), 4.34-4.42(1H, m), 4.57(2H, s), 6.85(1H, d),6.94(1H, t), 7.07(1H, d), piperidinyl]methyl]phenoxy]- 7.16(1H, d),7.24(1H, d), 7.35(1H, t) acetic acid 65 2-[[4-[[4-(2,4-Dichlorophenoxy)-(ES−ve) δ_((CD3OD)) 1.18-1.40(2H, m), 1.69-1.82(3H, m), 1.89-2.02(4H,m), 2.25(2H, 1-piperidinyl]methyl]-1- 511/513 d), 2.31-2.41(2H, m),2.63-2.73(2H, m), 2.98(2H, t), 3.34(2H, d), 4.34-4.44piperidinyl]methyl]- (1H, m), 4.52(2H, s), 6.98(1H, d), 7.14(1H, dd),7.30(1H, d), 7.39-7.51 benzenesulfonic acid (3H, m), 7.91-7.96(1H, m) 662-[[4-[[4-(2,4-Dichloro-3- 527/529 δ_((CD3OD)) 1.15-1.33(2H, m),1.66-2.02(7H, m), 2.12-2.37(7H, m), 2.57-2.68 methylphenoxy)-1- (2H, m),2.88-3.02(2H, m), 3.28-3.40(2H, m), 4.31-4.40(1H, m),piperidinyl]methyl]-1- 4.51(2H, s), 6.84(1H, d), 7.15(1H, d),7.39-7.50(3H, m), 7.90-7.96(1H, m) piperidinyl]methyl]- benzenesulfonicacid 68 Methyl 4-[[4-(2,4-dichloro-3- 429/431 methylphenoxy)-1-piperidinyl]methyl]-1- piperidineacetate 69 Methyl-4-[[4-(4-chloro-2-(ES−ve) methylphenoxy)-1- 393/395 piperidinyl]methyl]-1-piperidineacetate 70 Methyl 4-[[4-(2,4- 415/417 dichlorophenoxy)-1-piperidinyl]methyl]-1- piperidineacetate 71 Methyl4-[[4-(3,4-dichloro-2- 429/433 methylphenoxy)-1- piperidinyl]methyl]-1-piperidineacetate 72 Methyl 4-[[4-(3,4- 431/433 dichlorophenoxy)-1-piperidinyl]methyl]-4-hydroxy-1- piperidineacetate 74Methyl(2S)-2-(4-{[4-(3,4- 429/431 dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1- yl)propanoate 75 (αR)-Methyl-4-[[4-(4-chloro-2-(ES−ve) methylphenoxy)-1- 407/409 piperidinyl]methyl]-α-methyl-1-piperidineacetate 76 (αS)-Methyl-4-[[4-(4-chloro-2- (ES−ve)methylphenoxy)-1- 407/409 piperidinyl]methyl]-α-methyl-1-piperidineacetate 78 4-[[4-(2,4-Dichloro-3- 415/417 δ_((CDCl3))1.45-1.61(2H, m), 1.80-1.93(3H, m), 1.96-2.10(4H, m), 2.33(2H,methylphenoxy)-1- d), 2.38-2.48(2H, m), 2.47(3H, s), 2.71-2.82(2H, m),3.01(2H, t), 3.55-3.68(2H, piperidinyl]methyl]-1- m), 3.59(2H, s),4.44-4.54(1H, m), 6.96(1H, d), 7.27(1H, d) piperidineacetic acid 794-[[4-(4-Chloro-2- δ_((CD3OD)) 1.45-1.61(2H, m), 1.76-1.94(3H, m),1.97-2.09(4H, m), 2.20(3H, methylphenoxy)-1- s), 2.32(2H, d), 2.40(2H,t), 2.69-2.78(2H, m), 3.01(2H, t), 3.57-3.66(4H, piperidinyl]methyl]-1-m), 4.37-4.46(1H, m), 6.89(1H, d), 7.08-7.14(2H, m) piperidineaceticacid 80 [[4-(2,4-Dichlorophenoxy)-1- δ_((CD3OD)) 1.32-1.48(2H, m),1.67-1.80(3H, m), 1.84-1.96(4H, m), 2.20(2H, piperidinyl]methyl]-1- d),2.25-2.34(2H, m), 2.59-2.68(2H, m), 2.83-2.95(2H, m), 3.45-3.55(4H,piperidineacetic acid m), 4.34-4.42(1H, m), 6.98(1H, d), 7.14(1H, dd),7.30(1H, d) 81 4-[[4-(3,4-Dichloro-2- 415/417 δ_((CD3OD)) 1.52(2H, dd),1.79-1.94(3H, m), 1.99-2.08(4H, m), 2.32(3H, s), methylphenoxy)-1-2.38(2H, d), 2.48(2H, t), 2.77(2H, t), 3.01(2H, t), 3.55-3.64(4H, m),4.41-4.50 piperidinyl]methyl]-1- 4.50(1H, m), 6.93(1H, d), 7.28(1H, d)piperidineacetic acid 82 4-[[4-(3,4-Dichlorophenoxy)-1- 417/419piperidinyl]methyl]-4-hydroxy-1- piperidineacetic acid 83(2R)-2-(4-{[4-(3,4- 415/417 δ_((CD3OD)) 1.42-1.59(5H, m), 1.71-2.12(7H,m), 2.28-2.41(4H, m), 2.70-2.80(2H, Dichlorophenoxy)piperidin-1- m),2.93-3.14(2H, m), 3.49-3.62(3H, m), 4.37-4.46(1H, m),yl]methyl}piperidin-1- 6.91(1H, dd), 7.12(1H, d), 7.40(1H, t)yl)propanoic acid 84 (2S)-2-(4-{[4-(3,4- 415/417 δ_((CD3OD))1.44-1.60(5H, m), 1.73-2.12(7H, m), 2.30-2.43(4H, m), 2.71-2.81(2H,Dichlorophenoxy)piperidin-1- m), 2.93-3.14(2H, m), 3.50-3.62(3H, m),4.38-4.48(1H, m), yl]methyl}piperidin-1- 6.91(1H, dd), 7.12(1H, d),7.40(1H, d) yl)propanoic acid 85 (αR)-4-[[4-(4-Chloro-2- δ_((CD3OD))1.45-1.61(5H, m), 1.76-2.13(7H, m), 2.20(3H, s), 2.32(2H, d),methylphenoxy)-1- 2.41(2H, t), 2.69-2.79(2H, m), 2.94-3.14(2H, m),3.50-3.62(3H, m), 4.37-4.46(1H, piperidinyl]methyl]-α-methyl-1- m),6.90(1H, d), 7.08-7.14(2H, m) piperidineacetic acid 86(αS)-4-[[4-(4-Chloro-2- δ_((CD3OD)) 1.45-1.55(5H, m), 1.75-1.91(3H, m),1.95-2.09(4H, m), 2.18(3H, methylphenoxy)-1- s), 2.28(2H, d), 2.37(2H,t), 2.67-2.74(2H, m), 2.92-3.09(2H, m), 3.49-3.58(3H,piperidinyl]methyl]-α-methyl-1- m), 4.35-4.42(1H, m), 6.87(1H, d),7.06-7.12(2H, m) piperidineacetic acid 88 Methyl-4-[[4-(4-chloro-2-437/439 methylphenoxy)-1- piperidinyl]methyl]-α,α-dimethyl-1-piperidinepropanoate 89 Methyl 4-[[4-(2,4-dichloro-3- 471/473methylphenoxy)-1- piperidinyl]methyl]-α,α-dimethyl-1-piperidinepropanoate 91 4-[[4-(4-Chloro-2-methyl- 423/425δ_((CD3OD)) 1.14(6H, s), 1.32-1.47(2H, m), 1.65-1.80(3H, m), 1.92(4H,d), phenoxy)-1-piperidinyl]methyl]- 2.08(3H, s), 2.22(2H, d),2.27-2.36(2H, m), 2.59-2.68(2H, m), 2.86-2.99 α,α-dimethyl-1- (4H, m),3.37-3.45(2H, m), 4.26-4.34(1H, m), 6.78(1H, d), 6.97(1H, d),piperidinepropanoic acid 7.01(1H, q) 92 4-[[4-(2,4-Dichloro-3- 457/459δ_((CD3OD+NaOD)) 1.10(6H, s), 1.21-1.36(4H, m), 1.59-1.70(2H, m),1.77-1.87(2H, methylphenoxy)-1- m), 1.93-2.02(2H, m), 2.04-2.13(2H, m),2.18-2.23(2H, m), 2.29-2.38 piperidinyl]methyl]-α,α- 2.38(1H, m),2.44(3H, s), 2.48(2H, s), 2.64-2.73(2H, m), 2.87-2.93(2H,dimethyl-1-piperidinepropanoic m), 4.41-4.48(1H, m), 6.94(1H, d),7.24(1H, d) acid 95 Methyl 4-[[4-(3,4- 457/459 dichlorophenoxy)-1-piperidinyl]methyl]-1- piperidinepentanoate 96 Ethyl 4-[[4-(3,4- 485/487dichlorophenoxy)-1- piperidinyl]methyl]-1- piperidinehexanoate 974-[[4-(3,4-Dichlorophenoxy)-1- 429/431 δ_((CD3OD+NaOD)) 1.08-1.26(2H,m), 1.42-1.53(1H, m), 1.61-1.77(6H, m), piperidinyl]methyl]-1-1.85-1.97(4H, m), 2.05(2H, t), 2.13(2H, d), 2.17-2.24(2H, m),2.24-2.32(2H, piperidinebutanoic acid m), 2.56-2.66(2H, m), 2.87(2H, d),4.24-4.32(1H, m), 6.78(1H, dd), 6.99(1H, d), 7.27(1H, d) 984-[[4-(3,4-Dichlorophenoxy)-1- 443/445 δ_((CD3OD+NaOD)) 1.15-1.29(1H,m), 1.36(2H, q), 1.55-1.62(2H, m), 1.62-1.72(4H, piperidinyl]methyl]-1-m), 1.86-1.98(4H, m), 2.16(2H, t), 2.22(2H, d), 2.28(2H, t),2.61-2.70(2H, piperidinepentanoic acid m), 2.78(2H, t), 2.93(2H, t),3.36-3.44(2H, m), 4.27-4.34(1H, m), 6.79(1H, dd), 7.00(1H, d), 7.28(1H,d) 99 4-[[4-(3,4-Dichlorophenoxy)-1- 457/459 δ_((CD3OD+NaOD))1.22-1.42(4H, m), 1.49-1.71(5H, m), 1.74-1.85(4H, m),piperidinyl]methyl]-1- 1.94-2.07(4H, m), 2.14-2.27(4H, m), 2.29-2.40(4H,m), 2.67-2.77(2H, piperidinehexanoic acid m), 2.93-3.01(2H, m),4.35-4.44(1H, m), 6.90(1H, dd), 7.10(1H, d), 7.39 (1H, d) 1014-(3,4-Dichlorophenoxy)-1-[[1- 439/441 δ_((CD3OD)) 1.35(2H, dd),1.66-1.76(2H, m), 1.77-1.84(1H, m), 1.88-1.99(4H,[2-(2H-tetrazol-5-yl)ethyl]-4- m), 2.31(2H, d), 2.34-2.46(2H, m),2.66-2.89(4H, m), 3.12-3.18(2H, piperidinyl]methyl]-piperidine m),3.24-3.36(2H, m), 3.45(2H, d), 4.19-4.43(1H, m), 6.80(1H, dd), 7.02(1H,d), 7.29(1H, d) 103 N-[3-[4-[[4-(3,4- 532/534 δ_((CD3OD)) 1.14-1.30(2H,m), 1.53-1.76(5H, m), 1.80(2H, d), 1.86-1.97(2H, Dichlorophenoxy)-1- m),2.18(2H, d), 2.21-2.34(4H, m), 2.64(4H, t), 3.10(2H, d), 3.17(2H, t),piperidinyl]methyl]-1- 4.20-4.40(1H, m), 6.79(1H, dd), 7.00(1H, d),7.28(1H, d) piperidinyl]propyl]-1,1,1- trifluoro-methanesulfonamide 104N-[2-[4-[[4-(3,4-Dichloro-2- 532/534 δ_((CD3OD)) 1.27-1.43(2H, m),1.69-1.81(1H, m), 1.82-1.92(4H, m), 1.99-2.10(2H, methylphenoxy)-1- m),2.32(3H, s), 2.39-2.48(4H, m), 2.51-2.62(2H, m), 2.77(2H,piperidinyl]methyl]-1- t), 2.80-2.89(2H, m), 3.19(2H, d), 3.36(2H, t),4.43-4.53(1H, m), 6.92(1H, piperidinyl]ethyl]-1,1,1-trifluoro- d),7.28(1H, d) methanesulfonamide,

EXAMPLE 105

Pharmacological Analysis: Calcium flux [Ca²⁺]_(i) Assay

Human Eosinophils

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended (5×10⁶ mL⁻¹) and loaded with 5μM FLUO-3/AM+Pluronic F127 2.21 μl/mL (Molecular Probes) in lowpotassium solution (LKS; NaCl 118 mM, MgSO₄ 0.8 mM, glucose 5.5 mM,Na₂CO₃ 8.5 mM, KCl 5 mM, HEPES 20 mM, CaCl₂ 1.8 mM, BSA 0.1%, pH 7.4)for one hour at room temperature. After loading, cells were centrifugedat 200 g for 5 min and resuspended in LKS at 2.5×10⁶ mL⁻¹. The cellswere then transferred to 96 well FLIPr plates (Poly-D-Lysine plates fromBecton Dickinson pre-incubated with 5 μM fibronectin for two hours) at25 μl/well. The plate was centrifuged at 200 g for 5 min and the cellswere washed twice with LKS (200 μl; room temperature).

A compound of the Examples was pre-dissolved in DMSO and added to afinal concentration of 0.1% (v/v) DMSO. Assays were initiated by theaddition of an A₅₀ concentration of eotaxin and the transient increasein fluo-3 fluorescence (1_(Ex)=490 nm and 1_(Em)=520 nm) monitored usinga FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices,Sunnyvale, U.S.A.).

Compounds of the Examples were found to be antagonists if the increasein fluorescence induced by eotaxin (a selective CCR3 agonist) wasinhibited in a concentration dependent manner. The concentration ofantagonist required to inhibit the fluorescence by 50% can be used todetermine the IC₅₀ for the antagonist at the CCR3 receptor.

EXAMPLE 106

Human Eosinophil Chemotaxis

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended at 10×10⁶ mL-1 in RPMIcontaining 200 IU/mL penicillin, 200 μg/mL streptomycin sulfate andsupplemented with 10% HIFCS, at room temperature.

Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μlof either vehicle or compound (100× required final concentration in 10%DMSO). The chemotaxis plate (ChemoTx, 3 μm pore, Neuroprobe) was loadedby adding 28 μl of a concentration of eotaxin 0.1 to 100 nM (a selectiveCCR3 agonist over this concentration range) containing a concentrationof a compound according to the Examples or solvent to the lower wells ofthe chemotaxis plate. The filter was then placed over the wells and 25μl of eosinophil suspension were added to the top of the filter. Theplate was incubated for 1 hr at 37° C. in a humidified incubator with a95% air/5% CO, atmosphere to allow chemotaxis.

The medium, containing cells that had not migrated, was carefullyaspirated from above the filter and discarded. The filter was washedonce with phosphate buffered saline (PBS) containing 5 mM EDTA to removeany adherent cells. Cells that had migrated through the filter werepelleted by centrifugation (300×g for 5 mins at room temperature) andthe filter removed and the supernatant transferred to each well of a96-well plate (Costar). The pelleted cells were lysed by the addition of28 μl of PBS containing 0.5% Triton ×100 followed by two cycles offreeze/thawing. The cell lysate was then added to the supernatant. Thenumber of eosinophils migrating was quantified according to the methodof Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuringeosinophil peroxidase activity in the supernatant.

Compounds of the Examples were found to be antagonists of eotaxinmediated human eosinophil chemotaxis if the concentration response toeotaxin was shifted to the right of the control curve. Measuring theconcentration of eotaxin required to give 50% chemotaxis in the presenceor absence of compounds enables the apparent affinity of the compoundsat CCR3 to be calculated. Example % inhibition at 1 μM  1 96  4 90 10108 13 87

EXAMPLE 107

Guinea-Pig Isolated Trachea

(See for example, Harrison, R. W. S., Carswell, H. & Young, J. M. (1984)European J. Pharmacol., 106, 405-409.)

Male albino Dunkin-Hartley guinea-pigs (250 g) were killed by cervicaldislocation and the whole trachea removed. After clearing the adherentconnective tissue, the trachea was cut into six ring segments each threecartilage bands wide and then suspended in 20 mL organ baths containingKrebs-Henseleit solution of the following composition (mM): NaCl 117.6,NaH₂PO₄ 0.9, NaHCO₃ 25.0, MgSO₄ 1.2, KCl 5.4, CaCl₂ 2.6 and glucose11.1. The buffer was maintained at 37° C. and gassed with 5% CO, inoxygen. Indomethacin (2.8 μM) was added to the Krebs solution to preventdevelopment of smooth muscle tone due to the synthesis ofcyclo-oxygenase products. The tracheal rings were suspended between twoparallel tungsten wire hooks, one attached to an Ormed beam isometricforce transducer and the other to a stationary support in the organbath. Changes in isometric force were recorded on 2-channel Sekonic flatbed chart recorders.

Experimental Protocols

At the beginning of each experiment a force of 1 g was applied to thetissues and this was reinstated over a 60 minute equilibration perioduntil a steady resting tone was achieved. Subsequently, a cumulativehistamine concentration effect (E/[A]) curve was constructed at 0.5log₁₀ unit increments, in each tissue. The tissues were then washed andapproximately 30 minutes later, test compound or vehicle (20% DMSO) wasadded. Following an incubation period of 60 minutes a second E/[A] curvewas performed to histamine.

Contraction responses were recorded as a percentage of the first curvemaximum.

Data analysis

Experimental E/[A] curve data were analysed for the purposes ofestimating the potencies (p[A₅₀] values) of histamine in the absence andpresence of the test compound. Affinity (pA₂) values of test compoundswere subsequently calculated using the following equation:log(r−1)=log[B]+pA₂where r=[A]₅₀ in presence of test compound/[A]₅₀ in absence ofantagonist and [B] is the concentration of test compound. Compounds ofthe Examples were found to be H1 antagonists.

EXAMPLE 108

Histamine H1 receptor binding activity of compounds of the invention wasassessed by competition displacement of 1 nM [3H]-pyrilamine (Amersham,Bucks, Product code TRK 608, specific activity 30 Ci/mmol) to 2 μgmembranes prepared from recombinant CHO-K1 cells expressing the human H1receptor (Euroscreen SA, Brussels, Belgium, product code ES-390-M) inassay buffer (50 mM Tris pH 7.4 containing 2 mM MgCl₂, 250 mM sucroseand 100 mM NaCl) for 1 hour at room temperature. Example H1 pKi/[1328_S] 1 7.2  2 7.5  3 7.4  4 7.0  5 7.1  6 7.7  7 7.1  8 7.3  9 7.5 10 6.6 116.8 12 6.7 13 7.6 14 7.6 15 7.6 17 8.0 18 7.8 19 8.1 42 8.0 69 6.9 776.9 78 6.7 82 7.0 84 6.7 100  7.4 103  7.7

1. A compound of formula (I):

wherein: X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³; Y is a bond, C₁₋₆alkylene optionally substituted by C₁₋₄ alkyl or phenyl, phenyleneoptionally substituted by halogen, hydroxy, C₁₋₄ alkyl or C₁₋₄ alkoxy,or heterocyclylene optionally substituted by halogen, hydroxy, C₁₋₄alkyl or C₁₋₄ alkoxy; Z is CO₂Rb, NHS(O)₂CF₃, S(O)₂OH, OCH₂CO₂Rb ortetrazolyl; R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl; R² ishydrogen, C₁₋₆ alkyl, aryl or heterocyclyl; R^(a) and R^(b) are,independently, hydrogen or C₁₋₄ alkyl; or when R² is aryl orheterocyclyl; R^(a) may be C₂₋₃ alkylene forming a ring with an orthoposition on R²; R^(c) is hydrogen or hydroxy; wherein, unless statedotherwise, the foregoing aryl and heterocyclyl moieties are optionallysubstituted by: halogen, cyano, nitro, hydroxy, oxo, S(O)_(p)R⁴,OC(O)NR⁵R⁶, NR⁷R⁸, NR⁹C(O)R¹⁰, NR¹¹C(O)NR¹²R¹³, S(O)₂NR¹⁴R¹⁵,NR¹⁶S(O)₂R¹⁷, C(O)NR¹⁸R¹⁹, C(O)R²⁰, CO₂R²′, NR²²CO₂R²³, C₁₋₆ alkyl, CF₃,C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, OCF₃, C₁₋₆ alkoxy(C₁₋₆)alkoxy, C₁₋₆alkylthio, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl itselfoptionally substituted by C₁₋₄ alkyl or oxo, methylenedioxy,difluoromethylenedioxy, phenyl, phenyl(C₁₋₄)alkyl, phenoxy, phenylthio,phenyl(C₁₋₄)alkoxy, heterocyclyl, heterocyclyl(C₁₋₄)alkyl,heterocyclyloxy or heterocyclyl(C₁₋₄)alkoxy; wherein any of theimmediately foregoing phenyl and heterocyclyl moieties are optionallysubstituted with halogen, hydroxy, nitro, S(O)_(q)(C₁₋₄ alkyl),S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkylgroups may join to form a ring as described for R⁵ and R⁶ below), cyano,C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂(and these alkyl groups may join to form a ring as described for R⁵ andR⁶ below), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃; p and q are, independently, 0, 1or 2; R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁸,R¹⁹, R²⁰, R²¹ and R²¹ are, independently, hydrogen, C₁₋₆ alkyloptionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl, CH₂(C₂₋₆alkenyl), phenyl itself optionally substituted by halogen, hydroxy,nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ and these alkyl groups mayjoin to form a ring as described for R⁵ and R⁶ below, S(O)₂(C₁₋₄ alkyl),S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ and these alkylgroups may join to form a ring as described for R⁵ and R⁶ below, cyano,C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂and these alkyl groups may join to form a ring as described for R⁵ andR⁶ below, CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) or heterocyclyl itself optionallysubstituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂ and these alkyl groups may join to form a ring as described forR⁵ and R⁶ below, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂ and these alkyl groups may join to form a ring asdescribed for R⁵ and R⁶ below, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ and these alkyl groups may jointo form a ring as described for R⁵ and R⁶ below, CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃+;alternatively NR⁵R⁶, NR⁷R⁸, NR¹²R¹³, NR¹⁴R¹⁵, NR¹⁸R¹⁹, may,independently, form a 4-7 membered heterocyclic ring, azetidine,pyrrolidine, piperidine, azepine, morpholine or piperazine, the latteroptionally substituted by C₁₋₄ alkyl on the distal nitrogen; R⁴, R¹⁷ andR²³ are, independently, C₁₋₆ alkyl optionally substituted by halogen,hydroxy or C₃₋₁₀ cycloalkyl, CH₂(C₂₋₆ alkenyl), phenyl itself optionallysubstituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂ and these alkyl groups may join to form a ring as described forR⁵ and R⁶ above, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂ and these alkyl groups may join to form a ring asdescribed for R⁵ and R⁶ above, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may jointo form a ring as described for R⁵ and R⁶ above), CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃)or heterocyclyl (itself optionally substituted by halogen, hydroxy,nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ and these alkyl groups mayjoin to form a ring as described for R⁵ and R⁶ above, S(O)₂(C₁₋₄ alkyl),S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl), S(O)₂N(C₁₋₄ alkyl)₂ and these alkyl groupsmay join to form a ring as described for R⁵ and R⁶ above, cyano, C₁₋₄alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ andthese alkyl groups may join to form a ring as described for R⁵ and R⁶above, CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),C(O)(C₁₋₄ alkyl), CF₃ or OCF₃; or an N-oxide thereof, or apharmaceutically acceptable salt thereof; or a solvate thereof.
 2. Acompound as claimed in claim 1 wherein R¹ is phenyl optionallysubstituted with halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 3. A compound asclaimed in claim 1 wherein X is O.
 4. A compound as claimed in claim 1wherein R^(a) and R^(c) are both hydrogen.
 5. A compound as claimed inclaim 1 wherein Z is CO₂R^(b).
 6. A compound as claimed in claim 1wherein Y is a bond or alkylene optionally substituted by C₁₋₄ alkyl;R^(a) is hydrogen; and, R² is hydrogen, C₁₋₆ alkyl, phenyl optionallysubstituted by halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or NHC(O)(C₁₋₄ alkyl) orheterocyclyl optionally substituted by halogen, C₁₋₄ alkyl or C₁₋₄alkoxy.
 7. A compound as claimed in claim 1 wherein Y is phenyleneoptionally substituted by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy orheterocyclylene optionally substituted by halogen, C₁₋₄ alkyl or C₁₋₄alkoxy; R^(a) is hydrogen; and R² is hydrogen or C₁₋₄ alkyl.
 8. Aprocess for preparing a compound of formula (I) as claimed in claim 1,the process comprising: a) coupling a compound of formula (II):

with a compound of formula (III):

wherein L is a suitable leaving group; b) when R^(a) is hydrogen and Zis CO₂R^(b), reductive amination of a compound (II) with a compound offormula (IV):

wherein R^(b) is C₁₋₄ alkyl, in the presence of NaBH(OAc)₃ and aceticacid, or NaBH₃CN in a suitable solvent, optionally followed byhydrolysis of the ester group; c) when Y is a bond, R^(a) and R^(b) areboth hydrogen and Z is CO₂H, a three component coupling of a compound offormula (II) with compounds of formula (V) and (VI):

in a suitable solvent at a suitable elevated temperature; d) when Y is abond and Z is CO₂H, performing a nitrile hydrolysis on a compound offormula (XI):

e) when Z is tetrazol-5-yl, reacting a compound of formula (XI) with(CH₃)₃SiN₃ and (Bu₃Sn)₂O at an elevated temperature; f) when Z isNHS(O)₂CF₃, reacting a compound of formula (XII):

with triflic anhydride at a reduced temperature.
 9. A pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt thereof or solvate thereof as claimedin claim 1, and a pharmaceutically acceptable adjuvant, diluent orcarrier. 10-11. (canceled)
 12. A method of treating a chemokine mediateddisease state in a mammal suffering from, or at risk of, said disease,which comprises administering a compound of formula (I), or apharmaceutically acceptable salt thereof or solvate thereof as claimedin claim 1.